www.elsevier.com/locate/jhep
Journal of Hepatology 45 (2006) 856–867 

Review 

Cholangiocarcinoma: Modern advances in understanding 
a deadly old disease q 

Harmeet Malhi, Gregory J. Gores * 

Mayo Clinic College of Medicine, Rochester, MN, USA 

Cholangiocarcinomas are tumors that arise anywhere in the biliary tract, presumably of cholangiocyte origin. The global 
incidence of this rare disease is on the rise. Several known risk factors exist, and link chronic biliary inflammation to the 
pathogenesis ofcholangiocarcinoma. Among these, amplification of the epidermal growth factor receptor, the interleukin-6 
signaling pathway, inducible nitric oxide, erb-2, and cyclooxygenase-2 are well defined. Most patients present late, with a 
median survival of months. Although, imaging studies and clinical context often indicate cholangiocarcinoma, pathologic 
and cytologic diagnosis is difficult to obtain. Advanced cytologic tests with fluorescence in situ hybridization or digital 
image analysis can increase diagnostic sensitivity. Surgical resection is the current therapy of choice for both intrahepatic 
and ductal cholangiocarcinomas. However, the 5-year survival is poor, with 60 to greater than 90% recurrence rates. In a 
single center experience, liver transplantation with neoadjuvant chemoirradiation, for highly selected patients, has a 5-year 
disease free survival of greater than 80%. Future targeted therapies will depend on a better understanding of the cellular 
and molecular biology of cholangiocarcinomas. 

. 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. 
1. Introduction 
Cholangiocarcinomas are neoplasms with biliary 
epithelial cell or cholangiocytes differentiation, and 
are thought to arise from cholangiocytes. Most commonly, tumors occur at the biliary confluence (Klatskin or hilar cholangiocarcinoma), though in some 
instances tumors occur within the liver or distal to 
the hilum. The incidence is low, approximately 8 per 
million in the United States [1]. Though it is a rare 
malignancy, the incidence of cholangiocarcinoma is 
increasing globally [2,3], and it remains the second 
most common primary hepatobiliary malignancy. 
Since the description of Klatskin [4], several advances 
have been made in the understanding and treatment of 
this devastating disease. Several recognized risk factors 

Available online 25 September 2006 

q 

This work was supported by NIH Grant DK 41876 and the Mayo 
and Palumbo Foundations. 

* 

Corresponding author. Tel.: +1 507 284 0686; fax: +1 507 284 
0762. 

E-mail address: gores.gregory@mayo.edu (G.J. Gores ). 

account for a minority of cancers. Most cholangiocarcinomas arise in the absence of any known predisposition [5]. The molecular and cellular perturbations that 
characterize this malignant phenotype have been the 
focus of many investigators. These studies have partially elucidated abnormalities in growth regulatory 
genes in established cancers, and the mechanistic relationship between chronic biliary inflammation and 
cholangiocarcinogenesis. This information will ultimately help in the development of chemopreventive 
and therapeutic strategies. 

2. Classification 
Cholangiocarcinomas can be classified into three distinct categories by anatomic location. These are intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma 
and distal extrahepatic bile duct cancers (Fig.1). Hilar 
cancers, also known as Klatskin tumors, occur at the 
confluence of the right and left hepatic ducts, are the 
most frequent (50–60%) and can involve the liver by 

0168-8278/$32.00 . 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. 
doi:10.1016/j.jhep.2006.09.001 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
Fig. 1. Classification of cholangiocarcinoma. Cholangiocarcinomas are broadly classified into intrahepatic (also known as peripheral) or extrahepatic 
tumors. Eachis morphologically classified further into mass-forming, periductal-infiltrating or intraductal-growing. This classification alsocorresponds to 

the depiction of extrahepatic tumors as nodular, sclerosing or papillary. 

direct extension [6]. Because of the proximity of hilar 
and left and right branch tumors to the liver, they are 
included in intrahepatic cholangiocarcinomas in the 
SEER (Surveillance Epidemiology and End Results) 
database frequently used for epidemiologic studies. This 
practice is confusing and should be avoided. In this 
review intrahepatic cholangiocarcinoma refers only to 
tumors that originate within the hepatic parenchyma. 
Of the non-hilar tumors, 10% are intrahepatic and 
20–30% are extrahepatic distal bile duct tumors. Further 

classification of both intrahepatic and extrahepatic 
tumorsis based on gross tumor morphology. Three categories of cholangiocarcinoma have been identified 
based on their growth pattern: mass-forming, periductal-infiltrating, or intraductal-growing cholangiocarcinomas [7]. In an alternative system extrahepatic 
tumors alone are classified into nodular, sclerosing, or 
papillary (Fig. 1), a description that, respectively, 
matches the broader morphologic classification [8]. 
Hilar lesions are further classified as suggested by 


Fig.2. Bismuth-Corlette classificationof hilar cholangiocarcinoma.TypeI hilar cholangiocarcinoma involvesonlythe common hepatic duct, distal tothe 
confluenceoftheleftandrighthepaticducts(biliary confluence).TypeII involvesthebiliary confluence.TypeIIIa affectstherighthepaticductinaddition 
to the biliary confluence and Type IIIb involves the left hepatic duct in addition to the biliary confluence. Type IV tumors either involve both the right and 
left hepatic ducts in addition to the biliary confluence or are multifocal. 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
Bismuth-Corlette (Fig. 2), a pragmatic classification 
which corresponds to surgical decision making rather 
than tumor biology. Histologically, most tumors 
(>90%) are well to moderately differentiated tubular 
adenocarcinomas. The other outstanding histologic feature is the presence of a desmoplastic reaction. The 
fibrosis is variable, but may be profound in some cases, 
leading to a low diagnostic yield of random biopsies. 
Papillary adenocarcinoma, signet-ring carcinoma, squamous cell or muco-epidermoid carcinoma and a lymphoepithelioma-like form are rare histologic variants. 

3. Risk factors 
Risk factors for development of cholangiocarcinoma 
are age, primary sclerosing cholangitis (PSC), chronic 
choledocholithiasis, hepatolithiasis, bile duct adenoma, 
biliary papillomatosis, Caroli’s disease, choledochal 
cyst, thorotrast, smoking, hepatitis C virus infection, 
parasitic biliary infestation, and chronic typhoid carrier 
state [6]. Chronic hepatitis C virus (HCV) infection was 
reported as a risk factor for intrahepatic cholangiocarcinoma initially in the East [9]. Subsequently, it was identified as a risk factor even in the United States. HCV 
core protein has been detected in patient samples of 
cholangiocarcinoma [10]. Primary sclerosing cholangitis 
is an uncommon disorder, associated with inflammatory 
bowel disease, usually ulcerative colitis. The prevalence 
of cholangiocarcinoma in this population ranges from 
5to 15%, with a cumulative annual risk of 1.5% per year 
of disease [11,12].In East Asia, parasitic biliary infection 
with Clonorchis sinensis and Opisthorchis viverrini, 
acquired by the consumption of raw fish, is endemic in 
certain areas [5]. The parasite persists and progressively 
accumulates in the biliary system for years leading to a 
chronic inflammatory response and increased risk of 
cholangiocarcinoma. In one endemic area the adjusted 
prevalence odds ratio for cholangiocarcinoma was 
14.1% [13].A likely distinct typeofcholangiocarcinoma 
arises in the setting of fibropolycystic malformations of 
the biliary tree; indeed thereisa1% per year cumulative 
increase in cancer risk in patients with choledochal cysts. 
While biliary obstruction and inflammation play a role, 
other factors increase the risk of cancer, as cholangiocarcinomas can occur decades after surgical resection 
of the cyst [14]. One unifying feature of all these risk factors for cholangiocarcinoma is the presence of chronic 
biliary inflammation. 

4. Inflammation and carcinogenesis 
Molecular perturbations that lead to emergence of a 
cancerous phenotype involve the following pathways: 
growth autonomy, escape from senescence, unlimited 

replication, blockade of growth inhibitory signals, 
altered microenvironment and evasion of cell death. In 
chronically inflamed biliary epithelium several changes 
culminate in the upregulation of growth and prevention 
of cell death(Fig.3).Ina chronic inflammatory environment, epithelial cells are constantly stimulated to participate in the inflammation by generating chemokines and 
cytokines [15]. The cancers arising in this background 
retain secretion of these inflammatory mediators presumably because they provide growth and survival 
advantages. In this regard, interleukin 6 (IL-6) appears 
to be a pivotal cytokine for cholangiocarcinogenesis. 
Indeed cholangiocarcinoma cells constitutively secrete 
IL-6 [16]. In a presumably autocrine fashion, IL-6 activates pro-survival p38 mitogen activated protein kinase 
[17]. UpregulationofMcl-1,an anti-apoptotic proteinof 
the Bcl-2 family, and Akt activation are downstream 


Fig. 3. Molecular features of cholangiocarcinogenesis. Epithelial changes driven by chronic inflammation that promote tumor formation are 
depicted here. Autonomous proliferation is promoted by the following: 
interleukin 6 (IL-6), its receptor glycoprotein (gp130), epidermal growth 
factor receptor (EGFR), Her-2 (neu) gene product (c-erb-2), inducible 
nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2), and the 
oncoprotein K-ras. Evasion of apoptosis is promoted by: myeloid cell 
leukemia 1 (Mcl-1), Bcl-XL, Bcl-2, nitric oxide (NO) and cellular 
FLICE inhibitory protein (cFLIP). Escape from senescence is promoted 
by: p16INK4a, p53, p21, Mdm-2 and telomerase. Lastly, invasion and 
metastases are promoted by alterations of: E-cadherin, b-catenin, 
a-catenin, matrix metalloproteinase (MMP), vascular endothelial 
growth factor (VEGF) and aspartyl b-hydroxylase. 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
consequences of this cytokine signaling cascade [16,18]. 
Indeed, transforming growth factor b (TGFb), a tumor 
suppressor, can inhibit carcinogenesis by blocking IL-6 
signaling [19]. Loss of TGFb signaling, therefore, may 
allow full prooncogenic activity of IL-6. Furthermore, 
IL-6 also plays a role in senescence abeyance by promoting expression of telomerase [20]. Periductal-infiltrating 
and papillary cancers grow in an environment enriched 
in bile, suggesting not only resistance to the toxicity of 
bile but perhaps a tropism for bile. Indeed, bile acids 
transactivate the epidermal-derived growth factor receptor (EGFR) and also enhance expression of Mcl-1 [21]. 
Both IL-6 and EGFR have been shown to influence the 
expression of cyclooxygenase-2 (COX-2) [22]. COX-2 
and inducible nitric oxide synthase (iNOS) activation 
are the end result of this pro-inflammatory biliary 
epithelial milieu. Increased iNOS expression occurs in 
cholangiocytes in PSC and cholangiocarcinoma and elevated circulating nitrate levels occur in patient with liver 
fluke infestation [23]. Nitric oxide (NO) has known 
pleiotropic effects. NO can directly or via formation of 
reactive peroxynitrite species lead to deamination of 
guanine and DNA adduct formation promoting DNA 
mutations [24,25]. NO can also nitrosylate and inactivate DNA repair proteins permitting the accumulation 
of DNA mutations necessary for cancer development. 
NO can also nitrosylate caspase 9 leading to inhibition 
of apoptosis [26]. Importantly, iNOS promotes COX-2 
upregulation, presumably in the inflamed biliary tract, 
based on demonstration of this concept in immortalized, 
nonmalignant cholangiocytes [27]. iNOS can also stimulate expression of Notch, a developmentally important 
receptor, strongly implicated in the genesis ofpancreatic 
cancer [27]. Thus, iNOS has pleiotropic effects in biliary 
tract carcinogenesis. The ligand independent activation 
of EGFR by bile acids also leads to the activation of 
COX-2. COX-2 catalyzes the synthesis of prostanoids 
from arachadonic acid [28]. In colon cancer, COX-2 
derived prostanoids bind to prostanoid receptors activating the transcription factor b-catenin; which, if 
unregulated, is highly oncogenic. Likely similar signaling pathways also exist in cholangiocytes/cholangiocarcinomas. The role of b-catenin in cholangiocarcinoma, 
which plays a key role in hepatocellular and colorectal 
carcinoma [29], merits further investigation. 

Other molecular abnormalities associated with cholangiocarcinoma affect both growth factor receptor tyrosine kinase (RTK) and tumor suppressor genes. Besides 
IL-6/IL-6 receptor/glycoprotein 130, activating mutations and overexpression of EGFR, hepatocyte growth 
factor/c-met (HGF), erb-2, K-ras, and BRAF have been 
described in cholangiocarcinoma [30–34]. The proto-oncogene c-erbB-2 (also known as HER-2/neu) is activated in patients with cholangiocarcinoma. Furthermore, 
in experimental models, the sole introduction of this 
gene into a biliary epithelial cell line led to transforma

tion and recapitulation of several features of cholangiocarcinoma. Inactivation of tumor suppressor genes 
occurs frequently as well. Alterations in the p16INK4a 
and p14/MDM/p53 signaling pathway by homozygous 
deletion, exon mutations, promoter mutations, and 
methylation have been described in patients with PSC 
[35–38]. Promoter mutations leading to loss of transcriptional activity of the tumor suppressor p16INK4a 
occur not only in PSC but also in PSC-associated cholangiocarcinoma, suggesting a role in molecular carcinogenesis. Alterations in adhesion molecules and 
angiogenic factors that support the malignant phenotype have also been described. Decreased expression 
of E-cadherin, a-catenin, and b-catenin leads to weaker 
intercellular adhesion [39,40]. Overexpression of aspartyl (asparaginyl) b-hydroxylase, a molecule that favors 
tumor invasion, also occurs in cholangiocarcinoma 
[41]. Lastly, apomucins (MUC) play a role in immunophenotyping and have prognostic relevance [42]. MUC1 
expression is well described in intrahepatic cholangiocarcinoma. Tumors with high levels ofexpression, either 
mass-forming or periductal-infiltrating, have a poorer 
prognosis than intraductal-papillarytumors that display 
a lower level of MUC1 expression. In another surgical 
series, metastases 3 years after surgical resection were 
higher in the MUC1 positive group of patients with 
intrahepatic cholangiocarcinoma [43]. 

5. Clinical features 
The presentation of cholangiocarcinoma is primarily 
governed by anatomic location. Rarely, an asymptomatic cholangiocarcinoma is found during the evaluation of 
abnormal liver tests. Intrahepatic cholangiocarcinomas 
present as mass lesions; obstructive symptoms are rare. 
Fever, night sweats and weight loss may occur in addition to right upper quadrant abdominal pain. On the 
contrary, hilar and distal extrahepatic bile duct cancers 
present with symptoms of biliary obstruction, cholangitis and right upper quadrant pain. Other symptoms may 
coexist, related to hepatitis c infection, cirrhosis, or systemic metastases. 

6. Diagnosis 
Imaging modalities are the mainstay of diagnosis. 
Magnetic resonance imaging (MRI) with concurrent magnetic resonance cholangiopancreatography 
(MRCP) is the radiologic modality of choice (Fig. 4) 
[44–46].It allows visualization of the location and extent 
of biliary disease as well as hepatic parenchyma. Cholangiocarcinomas appear hypointense on T1-weighted 
images and hyperintense on T2-weighted images. Image 
enhancement can be observed using superparamagnetic 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
Fig. 4. Magnetic resonance imaging of a hilar cholangiocarcinoma. Representative MRI imaging with gadolinium enhancement with Feridex and with 
MRCP are shown. (A)A4 cm mass is seen centrally (right arrow) with abrupt cutoff of the left hepatic ducts. The mass and thickening also extend along 
the right posterior ductal system (left arrow). Intrahepatic bile ducts are dilated. (B) MRCP shows bilateral intrahepatic biliary dilatation with abrupt 
cutoff (arrow) corresponding to the 4 cm mass shown in (A). 

iron and delayed gadolinium images [47,48].MR 
angiography can be performed to assess vascular encasement [49]. Hepatic parenchyma, intrahepatic tumors, 
biliary dilatation, and lymph nodes can also be assessed 
via computed tomography (CT). CT angiography allows 
excellent visualization of the vasculature [50]. Ultrasound is non-specific; it may identify intrahepatic mass 
lesions, and bile duct dilatation proximal to the 
obstructing lesion. Endoscopic ultrasound guided 
regionallymph node sampling can be performed in early 
disease to assess respectability or eligibility for transplantation [51]. However, endoscopic aspiration of hilar 
masses is not recommended because of the potential for 
tumor seeding. 

Biliary instrumentation is necessary in the setting of 
biliary obstruction. It should also be performed to sample suspicious lesions for histologic and cytologic analyses. In one study, the sensitivity of routine cytology 
varied from 9 to 24% and specificity varied from 61 to 
100% [52]. In addition to routine pathology and cytology, advanced cytologic techniques can now be recommended for the evaluation of aneuploidy, a hallmark 
of cancer. These techniques are fluorescence in situ 
hybridization (FISH)(Fig.5)and digital imageanalysis 
(DIA) [53,54]. FISH utilizes fluorescent probes to identify chromosomal amplification (i.e., the actual number 
of a given chromosome in a cell) and DIA quantitates 
nuclear DNA as a ratio of normal ploidy (2N). The 
addition of either DIA or FISH to routine cytology 
increases the sensitivity without compromising the specificity for diagnosis of cholangiocarcinoma. The highest 
sensitivity for the diagnosis of malignant biliary stricture 
in patients with and without PSC is attained by the 
combination of DIA and FISH. Either DIA or FISH 
positivity had 67% sensitivity in the diagnosis of cholangiocarcinoma in PSC patients with normal cytology; 

however the specificity was 75%. When combined, 
DIA and FISH had a sensitivity of 14% in patients with 
PSC with normal cytology for the diagnosis ofcholangiocarcinoma while retaining a specificity of 98% (unpublished observation). 

Serologic testing is supportive and in most instances 
done prior to or concurrent with imaging studies, 
though not necessary for the diagnosis of cholangiocarcinoma. The focus of this discussion is on tumor associated markers and not routine liver test abnormalities. 
CA 19-9, CA 125 and CEA are the most studied tumor 
associated markers with cholangiocarcinomas. Of all 
three, CA 19-9 has the most utility. In patients with 


Fig. 5. Fluorescence in situ hybridization of biliary brushing. A 
representative fluorescence photomicrograph of biliary brushings from 
a patient with cholangiocarcinoma is shown here. Each colored spot 
represents one chromosome, therefore,2 spots per color are indicative of 
the normal diploid state. In this example, >2 spots are seen for more than 
one color (indicating more than one chromosome pair is abnormal), 
leading to a diagnosis of polysomy. 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
PSC a value of >100 U/ml has a sensitivity of 89% and 
specificity of 86%, and in patients without PSC the sensitivity is 53%, for the diagnosis of cholangiocarcinoma 
[7,55]. Increasing the cutoff to >129 U/ml in patients 
PSC provided a sensitivity of 78.6%, and improved the 
specificity to 98.5%, and a positive predictive value of 
56.6% [56]. In patients with advanced disease, the level 
may be strikingly elevated, though not universally. 
CEA and CA-125 are non-specific as they are elevated 
in patients with cholangiocarcinoma and other gut-derived malignancies, and they have a low sensitivity as 
well [57]. The caveat to the interpretation of an elevated 
CA 19-9 is the coexistence of bacterial cholangitis, which 
may not always be overt. Hepatolithiasis also commonly 
leads to increased levels of CA 19-9, and also CA 125 
and CEA. Therefore, cholangiocarcinoma should not 
be diagnosed on the basis of these tests alone except in 
patients with known risk factors or virtually diagnostic 
imaging studies. In an unrelated at-risk population, a 
study from Thailand demonstrated the utility of testing 
serum interleukin-6 levels in conjunction with CA 19-9 
in patients with chronic biliary parasitosis. A CA 19-9 
value >100 U/ml combined with an IL-6 value >50 pg/ 
ml had a sensitivity of 80% and accuracy of 76% [58]. 

In summary, there are multiple parallel diagnostic 
algorithms to confirm cancer in suspicious cases. Cancer 
should be carefully sought and confirmed or excluded in 
patients with high grade strictures, elevated CA 19-9 and 
suspicious masses. Though histologic diagnosis is the 
gold standard, percutaneous or trans-luminal approach 
is not recommended because of the risk of tumor seeding. Ideally, biliary tissue should be obtainedby ERCP. 
Non-diagnostic biopsy or cytology should not exclude 
the diagnosis of cholangiocarcinoma. Screening biliary 
instrumentation in stable, asymptomatic PSC patients 
is not recommended due to the concurrent risk of pancreatitis (>7% in patients with PSC, Dr. K. Lindor, personal communication), however, when clinically 
indicated advanced testing should be utilized to 
diagnose early cancers in PSC patients. Asymptomatic 
high risk patients may be surveyed non-invasively, such 
as with a serum CA 19-9 value and MRCP annually 
to achieve early cancer detection, although there are 
no outcome studies or cost-effectiveness information to 
advocate this approach. 

7. Staging 
There is no unified single staging system for all cholangiocarcinomas, reflecting the different patho-biology 
of intrahepatic and extrahepatic tumors. The staging 
of cholangiocarcinoma has also been dynamic. There 
have been several modifications and alternatives proposed, with the objective of improving the prognostic 
and therapeutic predictions for each cancer stage. For 

staging intrahepatic cholangiocarcinoma the proposed 
system correlates with survival after hepatic resection 
[59]. StageI diseaseisa solitary tumor without vascular 
involvement, Stage II disease is a solitary tumor with 
vascular encasement/invasion, Stage IIIA disease is multiple tumors with or without vascular involvement, 
Stage IIIB disease is any tumor with regional lymph 
node metastasis, and Stage IV diseaseis any tumor with 
distant metastases. 

The natural history of extrahepatic cholangiocarcinoma is short, and median survival ranges in months. The 
only effective treatment is surgical resection (and possibly liver transplantation), therefore, the evolution of 
staging systems for hilar cholangiocarcinoma has been 
towards a system that determines resectability. American Joint Committee on Cancer Staging system, based 
on the TNM classification, considers tumor pathology, 
and the presence of lymph node or extra-lymphatic 
metastases. It does not correlate with resectability. This 
led to the development and modification of the Memorial Sloan-Kettering staging system(Fig.6), also known 
as T-stage criteria for hilar cholangiocarcinoma [60].As 
shownin Fig.6,T1andT2 tumorsas well asT3 tumors 
involving the main portal vein are considered resectable, 
the latter only with portal reconstruction. This is based 
on the extent of biliary and vascular involvement, and 
correlates with resectability and survival. 

8. Therapy 
8.1. Curative surgical resection 
Surgicalresection is indicated in patients with cholangiocarcinoma in the absence of underlying liver or 
biliary tract disease. Solitary intrahepatic cholangiocarcinoma lesions are amenable to surgical resection. A 
partial hepatectomy with removal of the involved bile 
ducts is performed. Five-year patient survival ranges 
from approximately 20 to43%, the higher survival stems 
from careful patient selection [61–64]. In the remainder, 
recurrent disease is the norm. Strategies to prolong disease free survival using neoadjuvant therapy or adjuvant 
therapy with radiation or chemotherapy are not effective. The best predictors of survival are the absence of 
lymph node involvement, negative tumor margins up 
to 1cm, solitary lesions, and lack of microscopic vascular invasion. Perineural involvement and tumor site do 
not affect survival. Liver transplantation is contraindicated in these patients due to the universal recurrence 
rates and lack of effective neoadjuvant or adjuvant 
therapy. 

Extrahepatic lesions are evaluated for resection in the 
absence of local or distant metastases. For locally contained disease, respectability is primarily determined 
by the extent of biliary or vascular involvement. Fur


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
Fig. 6. T-stage modification of the Memorial Sloan-Kettering criteria for resectability of extrahepatic cholangiocarcinoma. T1 tumors do not involve 
vascular structures. They are limited to the hilum with unilateral involvement up to secondary biliary radicles.T2tumors involve the biliary confluence and 
additionally unilateral portal vein branch or secondary biliary radicles or ipsilateral lobar atrophy, all indicative to hilar disease with unilateral biliary or 
vascular involvement.T3 tumors have evidenceof bilateral biliary or vascular involvementin addition toa tumor at the biliary confluence.In some T3 
tumors the main portal vein alone is involved, in this case resection with portal vein reconstruction may be a possibility. 

thermore, resection is feasible only in the absence of 
underlying liver disease and PSC. The former, a contraindication to partial hepatectomy and the latter to prevent recurrence in predisposed at-risk epithelium. 
Bilobar involvement precludes curative surgery, as both 
the right and left lobes of the liver cannot be removed. 
This can manifest as bilateral portal vein branch 
involvement, involvement of the main portal vein, and 
bilateral involvement of secondary biliary radicals. Furthermore, unilobar involvement or atrophy with contralateral vascular involvement also represents disease 
advanced beyond respectability. Unilobar diseaseis considered resectable, even with ipsilateral encasement of 
the hepatic artery or portal vein branch, and/or involvement of ipsilateral secondary biliary radicals with 
associated lobar atrophy. A concomitant partial hepa

tectomy is the single most important factor leading to 
improved outcomes after resection of extrahepatic bile 
duct tumors [65,66]. Several strategies have been developed to improve outcomes. One such strategy is partial 
hepatic resection with concomitant en bloc resection of 
vascular structures and accompanied by reconstruction 
along with biliary excision for complex hilar tumors 
[60,67]. Indeed, even in patients with Bismuth-Corlette 
Stage II tumors involving the confluence of the right 
and left hepatic ducts, caudate lobe resection is recommended because the bile ducts from the caudate lobe 
drain directly into the confluence and cancer frequently 
extends up these ducts into the caudate lobe. Another 
strategy focuses on enhancing compensatory hepatic 
hypertrophy by pre-operative portal vein embolization 
to enable extended hepatectomy (resection of >=5 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
hepatic segments) [68,69]. Complete resection of distal 
bile duct tumors requires more extensive surgery, usually with pancreatoduodenectomy. Even with detailed preoperative stagingand curative intent, the5 year survival 
for hilar cholangiocarcinoma ranges from 20 to 40% 
[60,65,70]. Surgical tumor margin is the best predictor 
of survival; the RO group (no microscopic disease at 
surgical margin) of patients has the best 5 year survival 
in all published surgical series. Because of high rates of 
recurrence, several neoadjuvant therapies have been 
studied, including radiation, photodynamic therapy 
and chemotherapy. None of these have demonstrated 
clear benefit. Distal bile duct cancers have a 5 year survival rate of 37%. Survival is predicted as for proximal 
cancers by tumor free surgical margins and additionally 
by lymph node involvement. 

Resection in patients with PSC is discouraged as 
cholangiocarcinoma is often multifocal in this setting, 
the underlying parenchymal disease may preclude 
resection and recurrent disease with death following 
resection occurring in >90% of patients. In PSC 
patients with early cholangiocarcinoma, liver transplantation is the preferred definitive therapy (vide 
infra). In the absence of local or distant metastases, 
resectability of extrahepatic lesions is determined by 
the extent of involvement of the biliary tree and 
hepatic vasculature. 

8.2. Transplantation 
Unresectable cholangiocarcinoma is an emerging 
indication for liver transplantation, both deceased 
donor or living donor. The earliest case reports for 
transplantation for cholangiocarcinoma were dismal. 
Disease recurrence was the norm. There has been a 
resurgence in this modality based on recent experience. 
Two groups of patients stand to benefit from this 
modality. The first group are those with locally contained unresectable disease with otherwise normal biliary and hepatic structure and function. The other 
group is patients with underlying biliary inflammation, 
such as PSC, and/or hepatic dysfunction precluding 
surgery. The first description of a case series of 11 
patients transplanted for cholangiocarcinoma with neoadjuvant chemoirradiation demonstrated a 45% tumor 
free survival with a median follow up of 7.5 years 
(range 2.8–14.5 years) [71]. The experience of another 
specialized center in such a series of carefully selected 
patients has reported excellent disease free 5 year survival (82%) following a protocol of neoadjuvant external beam radiation therapy, trans-catheter intra-biliary 
radiation, chemotherapy and pre-transplant staging 
exploratory laparotomy [72,73] (Fig. 7). Indeed, over 
the same time period, with intent to treat analysis, survival with liver transplantation greatly exceeded that 
obtained with surgical resection. 

Fig. 7. Survival following transplantation for unresectable cholangio-
carcinoma. Atotal of 94 patients underwent staging surgery from 1993 to 
2006. Survival rate since time of diagnosis for patients who received liver 
transplantation (solid line) and those that were not transplanted (dotted 
line) because of the presence of extrahepatic disease on staging is shown. 
8.3. Adjuvant therapy 
Given the high rate of post-resection disease recurrence, adjuvant radiation therapy and chemotherapy 
have been explored as a means of improving disease free 
survival. There are no randomized controlled trials of 
either modality for post-operative therapy in patients 
with curative resection. In case series, radiation beam 
does not improve survival [74], and may even lead to 
hepatic decompensation [75]. Conflicting data exist 
regarding the role of chemotherapy. Some studies have 
shown improved survival whereas others have shown 
no benefit [76–78]. The authors do not advocate adjuvant therapy for this cancer. Brief mention should be 
made about the safety of neoadjuvant photodynamic 
therapy (discussed in detail below). In one case series, 
the safety ofbilioenteric anastomosis with photodynamic therapy pre-treated biliary epithelium has been 
demonstrated. 

8.4. Symptom palliation 
Since the natural history of this disease is short and 
most patients present with advanced disease, they are 
candidates mostly for palliative therapy. The goals then 
are symptom resolution and quality of life. Biliary 
obstruction is the major cause of morbidity in this population. This can be treated by a surgical, endoscopic or 
percutaneous approach. Surgical biliary bypass is associated with a high perioperative morbidity and mortality. Endoscopic biliary stenting is associated with 
negligible morbidity and mortality. Furthermore, it 
can be performed as an outpatient procedure. Biliary 
drainage can also be easily achieved percutaneously, 
however it has the disadvantage of external drains, bile 
leakage and patient discomfort. It may be the only 
option in patients with complete biliary obstruction. 
By either modality, adequate drainage of one functional 
hepatic lobe is sufficient to relieve cholestasis [79]. Stents 


H. Malhi, G.J. Gores / Journal of Hepatology 45 (2006) 856–867 
can be bare or coated and metal or plastic. Metal stents 
remain patent longer than plastic stents and should be 
considered in patients with an anticipated survival of 
less than 6 months. Plastic stents need to be changed 
periodically, often at 3 monthly intervals [80]. 

8.5. Tumor palliation 
Significant progress has been made in understanding 
this disease, and patients are being diagnosed earlier at 
specialized centers. However, a significant proportion 
of patients present with advanced disease. They are 
not candidates for curative surgery or transplantation. 
The palliative options, consisting of chemotherapy, radiation therapy, or photodynamic therapy are of limited 
benefit, as cholangiocarcinomas respond poorly to existing therapies. Trials of various combinations of these 
therapeutic options are lacking. 

Photodynamic therapy (PDT)isbased on the systemic administration of a photosensitizing agent and endoscopic tumor directed red laser light treatment resulting 
in selective tumor toxicity. Initial studies demonstrated 
the safety of this procedure in patients with advanced, 
non-resectable, hilar cholangiocarcinomas. Cholangitis 
and dermal phototoxicity related, respectively, to biliary 
instrumentation and the administration of photosensitizer occur in few patients. In patients with Bismuth-
Corlette III or IV tumors, and insufficient biliary 
drainage with endoscopic stent placement alone, PDT 
in addition to stenting led to successful biliary drainage 
and improved quality of life with no 30 day mortality. 
Several other case series have confirmed that the 
responses to photodynamic therapy include improved 
biliary drainage and quality of life [81–83]. Furthermore, in a prospective, open-label trial of PDT + endoscopic stenting compared to stenting alone, improved 
patient survival was demonstrated, 493 day median survival in the PDTgroup versus 98 daymedian survival in 
the stenting alone group(p < 0.0001) [81]. 

Other local ablative therapies including radiofrequency ablation for small intrahepatic cholangiocarcinoma [84–86], and trans-catheter arterial embolization 
are described. [87]. Initial trials of chemotherapy were 
5-fluorouracil (5FU) based. The response rates with 
5FU alone were 10% at best. Several 5FU based 
combinations, including doxorubicin, mitomycin C, 
methyl-CCNU, streptozotocin, and cisplatin + epirubicin, were of no added benefit [88,89]. This led to the 
use of gemcitabine, which has become the mainstay 
of chemotherapy [90–92]. Response rates ranging 
from 16 to 36% have been reported, based on different drug administration protocols. However, even 
with an initial 36% response rate, median survival 
was poor (6.5 months). It has also been tried in 
combination with other agents such as cisplatin, and 
5-fluorouracil, and the combination of Gemcita

bine±Cisplatin is now in Phase III trials. Several 
other agents are in Phase I/II trials. 

The emergence of novel therapeutic options based on 
tumor biology is the goal of the genomic and proteomic 
era of medicine. Several potential targets exist. Biological therapy targeting epidermal growth factor receptor 
(EGFR), commonly amplified in cholangiocarcinoma, 
is an attractive candidate. Similarly, chemoprevention 
with COX-2antagonists is successful in preventing cholangiocarcinoma growth in cell culture models and in 
experimental animal models. Other targets such as 
prostanoid antagonists or iNOS inhibitors need to be 
evaluated in experimental models. 

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