Cholangiocarcinoma

The right clinical information, right where it's needed

Last updated: Dec 19, 2017

 Table of Contents
Summary 3

Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Classification 5

Prevention 6

Diagnosis 7
Case history 7
Step-by-step diagnostic approach 7
Risk factors 10
History & examination factors 12
Diagnostic tests 13
Differential diagnosis 15
Diagnostic criteria 16

Treatment 18
Step-by-step treatment approach 18
Treatment details overview 20
Treatment options 22
Emerging 27

Follow up 28
Recommendations 28
Complications 28
Prognosis 28

Guidelines 29
Diagnostic guidelines 29
Treatment guidelines 29

Evidence scores 30

References 31

Images 36

Disclaimer 39
 Summary

◊ Painless jaundice, weight loss, and abdominal pain in patient >55 years old.

◊ Liver enzymes, blood levels of CA 19-9, CEA, CA-125; abdominal ultrasound, abdominal CT/MRI,
MR angiography, and cholangiography (ERCP, MRCP, percutaneous transhepatic catheterisation)
are used for evaluation.

◊ Surgical resection offers only potential cure.

◊ Chemotherapy has been shown to be relatively ineffective.

◊ Liver transplant is indicated in a small subset of patients.

 Cholangiocarcinoma Basics

Definition
Cholangiocarcinomas are cancers arising from the bile duct epithelium. These can be divided depending on
their location in the biliary tree: intrahepatic or extrahepatic (perihilar and distal). Perihilar tumours involving
BASICS

the bifurcation of the ducts are also known as Klatskin's tumours. More than 95% are adenocarcinomas.
Most are of the infiltrating nodular or diffusely infiltrating type. Purely nodular or papillary are less frequent
subtypes.

Epidemiology
Approximately two-thirds of cholangiocarcinomas occur in patients between 50 and 70 years of age, with a
slight male predominance.[4] The incidence of biliary tumours seems to have increased in the 10 years to
2007; however, the increase is probably due to improvement in data collection and analysis. The incidence
varies worldwide. The highest known rates occur in north-east Thailand (>80 per 100,000 population).[1]
High rates of biliary cancer are also seen in South American countries (Bolivia, Chile) and northern Japan.
Intermediate rates are seen in many European countries, and low rates are observed in the US, the UK,
India, Nigeria, and Singapore.[5] The lowest rates are seen in Canada (0.3 per 100,000).[1] In the US, New
Mexico has the highest incidence of biliary tree carcinoma (gallbladder carcinoma accounts for 8.5% of all
cancers).[6]

Aetiology
There is a close association between infection, inflammation, and cancer. Conditions that are associated with
an increased risk of developing intrahepatic cholangiocarcinoma include chronic liver disease due to hepatitis
B or C leading to cirrhosis,[7] alcoholic liver disease, non-specific cirrhosis, bile duct diseases (e.g., bile duct
adenoma, biliary papillomatosis, and congenital liver abnormalities such as choledochal cyst and Caroli’s
disease),[8] [9] choledocholithiasis, cholecystolithiasis, ulcerative colitis, and HIV.[10] [11] Primary sclerosing
cholangitis (PSC) has also been associated with high risk of cholangiocarcinoma, with a prevalence for
PSC patients ranging from 7% to 13%.[12] Risk factors for both intra- and extrahepatic cholangiocarcinoma
include chronic typhoid carriers, infection with liver flukes ( Chlonorchis sinensis and Opisthorchis ), heavy
drinking (>80 g of ethanol per day), exposure to certain toxins/medications (e.g., polychlorinated biphenyls
[PCBs],[13] isoniazid,[14] and oral contraceptive pills[15]), and the use of radionuclides (thorium dioxide, a
radioactive contrast agent used until the 1950s).[16] [17]

Pathophysiology
Cholangiocarcinomas are uncommon and, depending on the site of the cancer, the aetiological risk factors,
patient characteristics, and molecular biology of the tumour vary. Despite the remarkable advances that have
occurred in the understanding of cancer biology and genetics, little is known about the molecular biology
of biliary tract cancers. Reports have associated genetic mutations with the cellular mechanisms that have
an important role in the development of these tumours. Point mutations of K-ras and beta-catenin proto-
oncogenes, and alterations of p53, p16, APC, and DPC4 tumour suppressor genes by a combination of
chromosomal deletion, mutation, or methylation have been associated with biliary tract tumours.[18]

More than 95% of biliary tract cancers are adenocarcinomas. Most are of the infiltrating nodular or
diffusely infiltrating type. Purely nodular or papillary are less frequent subtypes. These tumours produce a

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Cholangiocarcinoma Basics
desmoplastic reaction resulting in a low neoplastic cellularity. This makes establishing a diagnosis difficult
with small biopsies. Staining for carcinoembryonic antigen (CEA), CA 19-9, or CA-50 aids in making a
pathological diagnosis.[6] [10] [12] [19]

BASICS
Signalling pathways, drivers of carcinogenesis, and potential targets for therapies include KRAS/MAPK,
EGFR, IL-6/STAT, IDH1/2, FGFR2, and MET signalling.[1] No oncogenic addiction loops have been
described so far. Molecular classification of iCCA based on gene signatures or molecular abnormalities is not
ready for clinical application.

Classification
European Association for the Study of the Liver[1]
Guidelines from the European Association for the Study of the Liver recommend that cholangiocarcinoma
should be sub-classified as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), where iCCA arises within
the liver parenchyma. The terms 'Klatskin's tumour' and 'extrahepatic tumour' are discouraged.

American Joint Commit tee on Cancer[2]

Tumours are classified according to their anatomical location: intrahepatic or extrahepatic (perihilar and
distal).

Bismuth-Corlet te: hilar cholangiocarcinoma[3]

The extent of duct involvement by perihilar tumours can be classified as suggested by Bismuth:

• Type 1 - tumours below the confluence of the left and right duct
• Type 2 - tumours reaching the confluence but not involving the left or right hepatic ducts
• Type 3 - tumours occluding the common hepatic duct and either the right (3a) or left (3b) hepatic duct
• Type 4 - tumours that are multi-centric or that involve the confluence and both the right and left hepatic
ducts.

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PREVENTION Cholangiocarcinoma Prevention

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Cholangiocarcinoma Diagnosis

Case history
Case history #1
A 65-year-old woman presents to her primary care physician with a 4-month history of intermittent
abdominal pain localised to the RUQ with radiation to the epigastrium; the pain increases with the
ingestion of fatty food and decreases with fasting. In the last 2 weeks the pain has been more frequent
and steady. The patient complains of nausea, pruritus, anorexia, and weight loss, which she relates to the
lack of appetite. At physical examination, there is RUQ tenderness and jaundice of the conjunctival sclera.
No lymphadenopathy or palpable masses are found.

Other presentations
The clinical diagnosis of biliary tract tumours is very difficult due to lack of specific symptoms. When the
classic symptoms (jaundice, weight loss, anorexia, and RUQ pain) appear, the disease is usually in a
more advanced stage. The clinical presentation depends largely on the location of the tumour, and the
presence or absence of obstructive jaundice. Patients with early tumours that have not yet obstructed
the bile duct may present with vague abdominal pain and LFT abnormalities. In advanced cases of distal
extrahepatic cholangiocarcinoma, a distended palpable gallbladder may be present without pain and
obstructive jaundice (Courvoisier's sign).

Step-by-step diagnostic approach

Cholangiocarcinoma usually presents late, with advanced disease. The clinical presentation depends
largely on the location of the tumour: that is, intrahepatic or extrahepatic (perihilar and distal). Some
cholangiocarcinomas are found unexpectedly as a result of an ultrasound scan or liver profile performed for
a different reason. However, imaging alone is not sufficient to make a diagnosis. Pathological diagnosis of
operative specimens is required for a definitive diagnosis.

DIAGNOSIS
History and physical examination
The typical patient is usually >50 years old. Other key risk factors that should be elicited during history-
taking include history of cholangitis, choledocholithiasis, cholecystolithiasis, other structural disorders
of the biliary tract, ulcerative colitis, primary sclerosing cholangitis, liver fluke infection, liver disease,
hepatitis C virus, HIV infection, hepatitis B virus, and exposure to thorium dioxide or other toxins/
medications (e.g., polychlorinated biphenyls [PCBs], isoniazid, oral contraceptive pills, and to chronic
typhoid carriers).

Intrahepatic cholangiocarcinoma:

• Usually presents as a mass lesion; obstructive jaundice symptoms are rare. Some non-specific
symptoms, such as abdominal discomfort, malaise, and nausea, can be present.
Extrahepatic cholangiocarcinoma (perihilar and distal):

• Usually presents with the symptoms of obstructive jaundice (around 90% of patients): pale stool,
dark urine, and pruritus. During the early stages of the tumour, when the biliary tract has not been

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 Cholangiocarcinoma Diagnosis
obstructed, some non-specific symptoms including vague abdominal pain, nausea, and malaise
can be present. In advanced disease, jaundice, pruritus, weight loss, anorexia, fatigue, abdominal
mass, hepatomegaly, and Courvoisier's sign (painless palpable gallbladder and jaundice) may be
present.[3] [27] [28]

Laboratory investigations
No blood tests are diagnostic for cholangiocarcinoma. LFTs should be ordered, as liver biochemical
abnormalities are consistent with obstructive jaundice. Certain serum tumour markers have shown some
utility as an aid to other diagnostic tests; however, they are not used as a screening test because of the
lack of sensitivity and specificity.

It is recommended that the following blood tests are ordered:

• Bilirubin (conjugated bilirubin is elevated in obstructive jaundice)

• Alk phos (usually elevated; suggests obstructive [or cholestatic] pattern of elevated LFTs)
• Gamma-GT (usually elevated; suggests obstructive [or cholestatic] pattern of elevated LFTs)
• Aminotransferase (may be minimally elevated)
• Prothrombin time (usually increased)
• CA 19-9 (elevated in up to 85% of patients)[20]
• CA-125 (elevated; detectable in up to 65% of patients)[20]
• CEA (elevated)

Imaging
A specific challenge in the management of cholangiocarcinoma is the lack of reliable imaging. No
consensus exists about the various combinations of imaging modalities. However, the definitive method
continues to be primarily ultrasound followed by CT or MRI.

The initial test to evaluate a patient with obstructive jaundice is an abdominal ultrasound.
[Fig-1]
DIAGNOSIS

This is because of the ubiquitous availability of this modality and the capacity to exclude common causes,
such as choledocholithiasis. Ultrasound allows for the visualisation of the intrahepatic and extrahepatic
biliary ducts, thus demonstrating the level of potential obstruction as well as the calibre and patency of the
portal vasculature.[20] However, the sensitivity of ultrasound in specifically detecting cholangiocarcinoma
is low. When additional criteria are employed, such as clinical history and presenting symptoms, a
focused ultrasound to evaluate the biliary tree and portal venous structures can have a high sensitivity.
However, used alone, ultrasound has a low level of accuracy in assessing any specific diagnoses.

Ultrasound is usually followed by an abdominal CT, which will confirm the presence of a mass and
whether or not there is obstruction, manifested as intrahepatic or extrahepatic ductal dilation. Abdominal
MRI is often utilised to differentiate between solid and cystic biliary contents. Furthermore, MRI can
provide additional information regarding tumour size, extent of bile duct involvement, vascular patency,
extrahepatic extension, nodal or distant metastases, and the presence of lobar atrophy. MRI diagnostic
performance is comparable to CT.[29] Pre-operative imaging with MR angiography is a non-invasive
method for staging cholangiocarcinoma, and therefore also helps to determine resectability.

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Cholangiocarcinoma Diagnosis
Imaging findings are then correlated with laboratory findings and if a provisional diagnosis of
cholangiocarcinoma is made, the patient will have further imaging by endoscopic retrograde
cholangiopancreatography (ERCP),
[Fig-2]

[Fig-3]

magnetic resonance cholangiopancreatography (MRCP), or percutaneous transhepatic catheterisation

(PTC).

The procedure of choice in further evaluating a cholangiocarcinoma is dependent on the need for biliary
decompression. ERCP is both diagnostic and therapeutic (procedures such as biopsy and decompressive
stent placement can be performed).[30] However, it also requires the ability to cannulate the ampulla
of Vater. If cannulation of the ampulla is not possible and biliary drainage is needed, then PTC is the
treatment of choice. MRCP is the recommended procedure if only anatomical visualisation of the bile
ducts distal to the stricture is required. The use of ERCP does not exclude MRCP. There is currently no
consensus in the literature with regard to choosing between these interventions.

ERCP is an endoscopic procedure. The endoscope is introduced into the second part of the duodenum
and contrast dye is injected into the bile ducts. If a tumour is present, a filling defect or area of narrowing
will be seen on the x-ray. During the procedure, samples of the tumour can be taken by brush or biopsy.
These should be sent to pathology for diagnosis. A bile sample can be sent for cytological analysis. An
ERCP also allows stent insertion for palliative purposes. The risks of ERCP include those associated with
sedation, damage or perforation of the gut wall, bleeding, allergic reaction to the dye, and pancreatitis.

MRCP can aid evaluation of the biliary tree proximal and distal to an obstruction. It can therefore provide
the surgeon with valuable information, such as if there is local invasion of the surrounding structures by
the tumour. MRCP has the advantage of being non-invasive and does not carry the risks that ERCP or
PTC do. The main disadvantage of MRCP is that it is diagnostic only and no therapeutic options can be
performed.

PTC is an invasive procedure that is used when the tumour causes complete obstruction of the biliary

DIAGNOSIS
tree and ERCP is unable to assess the biliary tree proximal to the tumour. It is also the imaging modality
of choice when the tumour is persistent or has recurred. If a tumour is found to be unresectable, a
stent can be placed during the procedure for palliation purposes. A bile sample can be taken during the
procedure and sent for cytological analysis.[20] The risks of PTC are bleeding, infection, and temporary or
permanent renal impairment.

Positron emission tomography (PET) is useful in the diagnosis of many cancers; however, current
literature cautions against the use of PET for determining the malignant potential of primary liver cancers.
Literature on PET more strongly supports the role of restaging of hepatobiliary malignancies and
identifying metastatic disease.[31]

Immunostaining
Cholangiocarcinoma can present as mixed with hepatocellular cancer. These tumours are more
aggressive. Immunostaining of pathological specimens to detect markers of hepatocellular
carcinoma (e.g., GPC3, HSP70, and glutamine synthetase) or progenitor cell features (e.g., K19,
EpCAM) is recommended to distinguish intrahepatic cholangiocarcinoma from mixed hepatocellular
cholangiocarcinoma if this information will change management.

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 Cholangiocarcinoma Diagnosis
Emerging tests
Optical coherence tomography (OCT) involves the use of infrared light to obtain scans that can correlate
with histology. Peroral cholangioscopy is currently in development for diagnostic imaging and for
pathological diagnosis. Duodenoscope-assisted cholangioscopy is an experimental procedure to evaluate
the inside of the bile duct using the duodenal approach, as would be used for a stent placement.

Risk factors
Strong
age >50 years
• Approximately two-thirds of cholangiocarcinomas occur in patients between 50 and 70 years of age.[4]

cholangitis
• Cholangitis increases the likelihood of intrahepatic cholangiocarcinoma, with an adjusted odds ratio
(OR) of 8.8 and 95% confidence interval (CI) of 4.9 to 16.0.[10] [11]
• Although, historically, cholangitis has been related to an increased risk of extrahepatic
cholangiocarcinoma, no data are available on the strength of this association.

choledocholithiasis
• Choledocholithiasis increases the risk of intrahepatic cholangiocarcinoma, with an adjusted OR of 4.0,
95% CI of 1.9 to 8.5.[11]
• No data are available with regard to the association with extrahepatic cholangiocarcinoma, but a
historical association exists.

cholecystolithiasis
• Cholecystolithiasis increases the risk of intrahepatic cholangiocarcinoma, with an OR of 4.0, 95% CI of
2.0 to 7.99.[10]
DIAGNOSIS

• No data are available with regard to the association with extrahepatic cholangiocarcinoma, but a
historical association exists.

other structural disorders of the biliary tract

• Examples include bile duct adenoma, biliary papillomatosis, choledochal cyst, and Caroli's disease
(non-obstructive dilation of the biliary tract).[20]

ulcerative colitis (UC)

• UC increases the risk of intrahepatic cholangiocarcinoma, with an OR of 2.3, 95% CI of 1.4 to 3.8.[11]
• No data are available with regard to the association with extrahepatic cholangiocarcinoma, but a
historical association exists.

primary sclerosing cholangitis (PSC)

• PSC has been associated with high risk of cholangiocarcinoma, with its prevalence in PSC patients
ranging from 7% to 13%.[12] It also has a strong association with UC, another risk factor of
cholangiocarcinoma; between 60% and 80% of all patients with PSC have a co-existing UC. The
incidence of cholangiocarcinoma may be higher in patients with both conditions.[21]

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Cholangiocarcinoma Diagnosis
non-specific cirrhosis
• Non-specific cirrhosis has a stronger association with intrahepatic cholangiocarcinoma, with an OR of
27.2, 95% CI of 19.9 to 37.1.[11]

alcoholic liver disease

• Alcoholic liver disease increases the risk of intrahepatic cholangiocarcinoma, with an OR of 7.4, 95%
CI of 4.3 to 12.8.[11]
• Heavy drinking (>80 g of ethanol per day) has a strong association with intrahepatic
cholangiocarcinoma (OR of 6.0, 95% CI of 2.3 to 16.7) and extrahepatic cholangiocarcinoma (OR of
4.0, 95% CI of 1.7 to 10.2).[22]

liver fluke infection

• Chlonorchis sinensis increases the risk of intrahepatic cholangiocarcinoma and extrahepatic
cholangiocarcinoma, with a relative risk (RR) of 2.7, 95% CI of 1.1 to 6.3.[7]
• Chlonorchis sinensis and Opisthorchis viverrini infestation have been related in East Asian countries
with higher incidence of cholangiocarcinoma; the activation of the host immune system and the chronic
inflammatory state are proposed as the initial factors in the epithelial transformation to cancer.

chronic typhoid carrier

• In South-East Asia, where incidence of cholangiocarcinoma is increased, chronic typhoid carriers have
a sixfold risk of developing a hepatobiliary malignancy.[20]

hepatitis C virus (HCV)

• HCV infection has a strong association with intrahepatic cholangiocarcinoma, with an OR of 6.1, 95%
CI of 4.3 to 8.6.[11]
• No association was found with extrahepatic cholangiocarcinoma, with an OR of 4.5, 95% CI of 0.8 to
45.7.[11]

HIV

DIAGNOSIS
• HIV infection has been related to intrahepatic cholangiocarcinoma, with an OR of 5.9, 95% CI of 1.8
to 18.8.[11] HIV infection is known to increase the prevalence of cholangitis either directly or via other
opportunistic infections (e.g., cytomegalovirus).[23]
• HIV-related cholangitis could lead to changes similar to those induced by other inflammatory
conditions of the bile duct that eventually result in cancer; it could be a confounding factor because
HIV tends to co-occur with HCV infection.

hepatitis B virus (HBV)

• HBV-infected patients have been found to have a higher prevalence of intrahepatic
cholangiocarcinoma in several studies.[7] [24] [25]
• Other studies have not found any association between intrahepatic cholangiocarcinoma and HBV
infections; however, the number of cases used was small.[11]

exposure to thorium dioxide

• Exposure to thorium dioxide, such as thorotrast, a radioactive contrast agent used until the 1950s,
results in an increased incidence of cholangiocarcinoma.[17]

Weak

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 Cholangiocarcinoma Diagnosis
diabetes
• No clear association has been found.[10] [11]

cigaret te smoking
• No clear association has been found.[10] [11] Smoking seems to increase the risk of
cholangiocarcinoma in patients with PSC.[26]

exposure to toxins/medicines
• Occupational exposure to polychlorinated biphenyls (PCBs),[13] isoniazid,[14] oral contraceptives,[15]
and chronic typhoid carriers poses an increased risk of cholangiocarcinoma.[20]

male sex
• There is a slight male predominance.[4]

History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Key risk factors include age >50 years, cholangitis, choledocholithiasis, cholecystolithiasis, other
structural disorders of the biliary tract, ulcerative colitis, primary sclerosing cholangitis, liver fluke
infection, liver disease, hepatitis C virus, HIV infection, hepatitis B virus, and exposure to thorium
dioxide.

painless jaundice (common)

• 90% of patients.[6]

weight loss (uncommon)

• 35% of cases.[32]
DIAGNOSIS

abdominal pain (uncommon)

• 35% of cases.[32]

Other diagnostic factors

pruritus (uncommon)
• 26% of cases.[32]

triad of fever, jaundice, and RUQ pain (uncommon)

• Features of acute cholangitis. Occurs in 10% of cases.[32]

palpable gallbladder (uncommon)

• Rare.

hepatomegaly (uncommon)
• Rare.

dark urine (uncommon)

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Cholangiocarcinoma Diagnosis
• If obstructive jaundice is present.

pale stools (uncommon)

• If obstructive jaundice is present.

Diagnostic tests
1st test to order

Test Result
serum bilirubin elevated
• Conjugated bilirubin is elevated in obstructive jaundice.
serum alk phos elevated
• Suggests obstructive (or cholestatic) pattern of elevated LFTs.
serum gamma-GT elevated
• Suggests obstructive (or cholestatic) pattern of elevated LFTs.
serum aminotransferase elevated
• May be minimally elevated. High elevations are seen more frequently
in intrahepatic cholangiocarcinoma with direct hepatic invasion.[27]
serum prothrombin time increased
• Caused by prolonged obstruction of the common bile or hepatic duct
and a subsequent reduction in fat-soluble vitamins (A, D, E, and K).
serum CA 19-9 elevated
• Elevated in up to 85% of patients with cholangiocarcinoma.[20] Also
elevated in pancreatic or gastric malignancy, in severe hepatic injury
from any cause, and with obstructive jaundice without malignancy.
However, if levels continue to be raised after biliary decompression,
this suggests malignancy. In patients with primary sclerosing

DIAGNOSIS
cholangitis and suspected cholangiocarcinoma, a value of >100 units/
mL has a sensitivity of 75% and specificity of 80%.[33]
serum CEA elevated
• Also elevated in inflammatory bowel disease, other tumours, and
severe liver injury.
serum CA 19-9 + (40 times CEA) >40 kilo-units/L
• Equation used to calculate the likelihood of a tumour progression.
Positive predictive value of 100% in predicting progression to
cholangiocarcinoma.[34]
serum CA-125 elevated
• Detectable in up to 65% of patients.[20]
abdominal ultrasound diagnosis suspected
when intrahepatic ducts
• Identifies malignant versus benign lesions with a sensitivity of 92%
are dilated; intrahepatic
and a specificity of 93%.[35]
cholangiocarcinoma may
[Fig-1]
be seen as a mass lesion

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 Cholangiocarcinoma Diagnosis

Other tests to consider

Test Result
abdominal CT intrahepatic mass lesion,
dilated intrahepatic
• CT identifies a primary lesion in approximately 59% of cases.[36]
ducts, and localised
lymphadenopathy may be
seen

abdominal MRI local extent of tumour (the

tumour is hypointense
• MRI is often utilised to differentiate between solid and cystic biliary
in T1- and hyperintense
contents. Furthermore, MRI can provide additional information
in T2-weighted image),
regarding tumour size, extent of bile duct involvement, vascular
hepatic parenchymal
patency, extrahepatic extension, nodal or distant metastases, and
abnormalities, and liver
the presence of lobar atrophy. MRI diagnostic performance is
metastases can be seen
comparable to CT.[29]
MR angiography staging tool
• Pre-operative imaging with MR angiography is a non-invasive
method for staging cholangiocarcinoma, and therefore also helps to
determine resectability.
ERCP a filling defect or area of
narrowing will be seen if a
• Tissue diagnosis in 40% to 70%.[20]
tumour is present
[Fig-2]

[Fig-3]
• Staining for carcinoembryonic antigen (CEA), CA 19-9, or CA-50 aids
in making a pathological diagnosis.[6] [10] [12] [19]
MRCP can show extent of duct
involvement above and
• Sensitivity comparable to PTC.[37] MRCP has the advantage of
below the obstruction
being non-invasive and does not carry the risks that ERCP or PTC
do. The main disadvantage of MRCP is that it is diagnostic only, and
no therapeutic options can be performed.
DIAGNOSIS

percutaneous transhepatic catheterisation (PTC) may show dilated

intrahepatic ducts with
• Diagnostic sensitivity as high as 92%.[38] An invasive procedure that
irregular filling defects
is used when the tumour causes complete obstruction of the biliary
and strictures at site of
tree, and ERCP is unable to assess the biliary tree proximal to the
occlusion
tumour.
positron emission tomography (PET) evidence of malignancy
• PET is useful in the diagnosis of many cancers; however, current
literature cautions against the use of PET for determining the
malignant potential of primary liver cancers. Literature on PET more
strongly supports the role of restaging hepatobiliary malignancies and
identifying metastatic disease.[31]
• Sensitivity is low in cholangiocarcinoma.
Immunostaining may help to distinguish
intrahepatic
• Immunostaining of pathological specimens to detect markers of
cholangiocarcinoma from
hepatocellular carcinoma (e.g., GPC3, HSP70, and glutamine
mixed hepatocellular
synthetase) or progenitor cell features (e.g., K19, EpCAM) is
cholangiocarcinoma
recommended to distinguish intrahepatic cholangiocarcinoma from
mixed hepatocellular-cholangiocarcinoma tumours if this information
will change management.

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Cholangiocarcinoma Diagnosis

Emerging tests

Test Result
optical coherence tomography (OCT) variable
• Infrared light used to obtain scans that can correlate with histology.
peroral cholangioscopy variable
• In development for diagnostic imaging and for pathological diagnosis.
duodenoscope-assisted cholangioscopy variable
• Experimental procedure to evaluate the inside of the bile duct using
the duodenal approach, as would be used for a stent placement.

Differential diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
Hepatocellular carcinoma • Patients generally present • The same imaging
(HCC) with symptoms of advancing modalities are used.
cirrhosis, with jaundice, • HCC is the more likely
ascites, asterixis, pedal diagnosis if the lesion is
oedema, periumbilical peripheral and cirrhotic
collateral veins, and possibly parenchyma is present, but
alcoholic stigmata. There ultimately it will be pathology
may be a history of variceal that distinguishes between
bleeding and episodes of the two tumours.
hepatic encephalopathy.

Ampullary carcinoma • Presents with many of • Diagnosis of ampullary

the same features as lesion is made using ERCP;
cholangiocarcinoma, with however, confirmation
jaundice, pruritus, anorexia, of malignancy requires

DIAGNOSIS
weight loss, and a distended, histological examination.
palpable gallbladder.
• Patients may have
diarrhoea, which is not
commonly associated with
cholangiocarcinoma.

Pancreatic carcinoma • A characteristic feature • The same imaging

is significant weight modalities are used. It
loss. Patients may also may be clear from CT or
experience epigastric MRI that the tumour is
or back pain, which is arising from the body of the
not commonly seen with pancreas, but more difficult
cholangiocarcinoma. to distinguish if the tumour is
arising from the head of the
pancreas. Ultimately it is the
histology that will distinguish
between the two tumours.

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 Cholangiocarcinoma Diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
Choledocholithiasis • Gallstones in the common • ERCP will definitively
bile duct (CBD) can present diagnose and treat this
with signs and symptoms condition.
of obstructive jaundice. In
addition, the presence of
gallstones in the CBD and
cystic duct obstruction can
mimic Courvoisier's sign
(presents with enlarged
gallbladder, which would
be similar to an obstruction
secondary to tumour in the
bile duct). Gallstones in the
gallbladder can cause no
symptoms.

Cholangitis • This typically presents as a • Clinical diagnosis of a

triad of fever, RUQ pain, and consequence of biliary
jaundice. obstruction regardless of
• Although a common cause cause.
for the infection can be • WBC count is elevated
gallstones in the common and imaging (CT, MRCP,
bile duct, the infection can ERCP) demonstrates biliary
also be superimposed upon obstruction.
obstruction caused by a • Blood cultures may be
tumour. positive for aetiological
organism.

Diagnostic criteria
American Joint Commit tee on Cancer TNM staging of bile duct
DIAGNOSIS

malignancy[2]
Tumours are staged according to their anatomical location: intrahepatic or extrahepatic (perihilar and distal).

TNM classification of intrahepatic bile ducts:

• T (primary tumour)

• TX: primary tumour cannot be assessed

• T0: no evidence of primary tumour
• Tis: carcinoma in situ (intraductal tumour)
• T1: solitary tumour without vascular invasion
• T2a: solitary tumour with vascular invasion
• T2b: multiple tumours, with or without vascular invasion
• T3: tumour perforating the visceral peritoneum or involving the local extrahepatic structures by
direct invasion
• T4: tumour with periductal invasion

• N (regional lymph nodes)

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Cholangiocarcinoma Diagnosis

• NX: regional lymph nodes cannot be assessed

• N1: no regional lymph node metastasis
• N2: regional lymph node metastasis present

• M (distant metastasis)

• M0: no distant metastasis

• M1: distant metastasis

TNM classification of extrahepatic bile ducts:

• T (primary tumour)

• TX: primary tumour cannot be assessed

• T0: no evidence of primary tumour
• Tis: carcinoma in situ
• T1: tumour confined to the bile duct, with extension up to the muscle layer or fibrous tissue
• T2a: tumour invades beyond the wall of the bile duct to surrounding adipose tissue
• T2b: tumour invades adjacent hepatic parenchyma
• T3: tumour invades unilateral branches of the portal vein or hepatic artery
• T4: tumour invades main portal vein or its branches bilaterally; or the common hepatic artery;
or the second-order biliary radicles bilaterally; or unilateral second-order biliary radicles with
contralateral portal vein or hepatic artery involvement

• N (regional lymph nodes)

• NX: regional lymph nodes cannot be assessed

• N0: no regional lymph node metastasis
• N1: regional lymph node metastasis (including nodes along the cystic duct, common bile duct,
hepatic artery, and portal vein)

DIAGNOSIS
• N2: metastasis to periaortic, pericaval, superior mesenteric artery, and/or coeliac artery lymph
nodes

• M (distant metastasis)

• M0: no distant metastasis

• M1: distant metastasis

Staging laparoscopy is also performed to determine the presence of peritoneal or superficial liver metastases
in patients who have potentially resectable disease.[39] [20]

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 Cholangiocarcinoma Treatment

Step-by-step treatment approach

General approach
It is recommended that management of a patient with cholangiocarcinoma be carried out by a multi-
disciplinary team consisting of specialist surgeons, radiologists, oncologists, and palliative care
consultants.

Surgical resection is the only potential cure, but only a small percentage of patients are successfully
treated this way. Other options include liver transplant (although only a few select patients qualify for this),
chemotherapy, and/or radiotherapy and palliation.

Although management for intrahepatic and extrahepatic cholangiocarcinoma does differ, patients can
generally be divided into those who have resectable tumours and those who do not.

Resectable tumours
Patients who have resectable tumours have:

• No evidence of metastases, regional lymph node involvement, portal vein extension, or bilateral
ductal extension
• Imaging indicating the possibility that the surgeon will be able to resect with clear margins and be
able to clear at least one side of the biliary tree of tumour
• No comorbidities that prevent the patient from undergoing surgery.
The goal of surgery is to achieve negative margins (there is a 20% to 43% 5-year survival rate if this
occurs).[40] [41] [42] [43] Positive predictors of survival are negative margins, absence of lymph node
involvement, solitary lesions, and lack of vascular invasion. Hilar involvement lowers medial survival to 12
to 24 months, from 18 to 30 months for more distal tumours.

Intrahepatic tumours

• Patients with a resectable intrahepatic cholangiocarcinoma should undergo a partial liver resection.
• If resection is successful and there is no local residual disease, patients can be followed up by
observation. There is no adjuvant regimen that is proven to improve survival.
• If, after resection, there is some residual disease (i.e., positive margins), it is recommended
that the multi-disciplinary team consider adjunctive therapy on an individual patient basis. The
available options are possible further resection, ablative therapy, or chemotherapy with or without
radiotherapy.
• No recommended standard chemotherapy regimen is currently available. Chemotherapy is usually
an option if negative margins are not obtained following resection. If negative margins are obtained,
the role of chemotherapy is controversial.[44]
Extrahepatic tumours

• For patients with an extrahepatic cholangiocarcinoma, the type of surgery depends on the location
TREATMENT

of the tumour:

• Tumours that are within the proximal third of the extrahepatic biliary tree should be
removed by hilar resection, partial hepatectomy combined with caudate lobe resection, and
lymphadenectomy.[45]

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Cholangiocarcinoma Treatment
• Tumours within the mid-third should undergo major bile duct excision with lymphadenectomy.
Either partial hepatectomy or pancreaticoduodenectomy may be required to achieve
complete tumour clearance.
• Distal extrahepatic tumours should be removed with pancreaticoduodenectomy with
lymphadenectomy.
• Tumours can be resected by portal vein resection when the portal vein is involved. This
approach confers a marginal benefit over not undergoing resection.[46]
• If the tumour is resected successfully and there are no positive lymph nodes, the patient has a
choice either to undergo chemotherapy with radiotherapy or to have no further treatment.
• If resection margins are positive or lymph nodes are involved, the patient should be offered
chemotherapy, either alone or in conjunction with radiotherapy.[47] [48]
Pre-operative portal vein embolisation may contribute to reduction of complications and surgery-related
mortality, and may be considered for patients undergoing right hepatectomy or larger resection, such as
trisegmentectomy.[49] [50] It may also be considered for those patients undergoing hepatectomy with a
planned resection rate exceeding 50% to 60%, especially those with a jaundiced liver.

Pre-operative biliary drainage has been used to reduce morbidity and mortality in patients with obstructive
jaundice. However, there are several studies that are against the routine use of pre-operative surgical
endoscopic or percutaneous stenting.[51] [52] [53] Despite this evidence, pre-operative biliary drainage
remains a controversial procedure, and is still advocated by several centres.[54] Generally, if patients
have a resectable lesion and surgery can be done within a few days of diagnosis, this procedure is not
required. Pre-operative biliary drainage can be done using covered or uncovered metallic stents, and
current evidence indicates that covered stents are better for a longer duration of patency.[55]

Unresectable tumours
Criteria that make a tumour unresectable are:[56]

Patient factors

• Comorbidity
• Coexistent hepatic cirrhosis.
Tumour-related factors

• Tumour extension to secondary biliary radicles

• Encasement or occlusion of main portal vein proximal to the bifurcation
• Atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusion
• Atrophy of one hepatic lobe with contralateral tumour extension to secondary biliary radicles
• Unilateral tumour extension to secondary biliary radicles with contralateral portal vein branch
encasement or occlusion
• Histologically proven metastasis to regional lymph nodes
• Lung, liver, or peritoneal metastasis.
Liver transplant
TREATMENT

• Results are mixed for liver transplant, but it can be supported in highly selected groups of patients
with unresectable disease:

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 Cholangiocarcinoma Treatment

• Patients with locally advanced disease (typically hilar) involving the surrounding large
vessels (portal vein, hepatic artery) and extension to secondary biliary radicles
• Patients with underlying biliary inflammation (e.g., primary sclerosing cholangitis) or hepatic
dysfunction precluding surgery.[57] [58] [59]
• Regional lymph node involvement and the presence of distant metastasis exclude the patient from
liver transplant.
• Most high-volume centres performing this procedure use neoadjuvant chemotherapy or
chemoradiotherapy, with the thought that it will limit recurrence from metastasis and lymphatic
spread.[60] 1[C]Evidence
Chemotherapy ± radiotherapy

• Each patient is considered on an individual basis, but those patients who are not transplant
candidates are typically offered chemotherapy with gemcitabine plus a platinum compound,[47] [48]
either alone or in combination with radiotherapy. Due to the limited response rate in this tumour,
treatment is generally discontinued if progression of disease is confirmed by imaging. A number of
tumours that are downstaged may be considered resectable post chemoradiotherapy.[62]
• In patients with unresectable cholangiocarcinoma, transarterial chemotherapy-based treatment may
confer a survival benefit of 2-7 months compared with systemic therapy.[63]
Palliative therapy

• The alternative option for unresectable tumours is palliative care. The goal of palliation is symptom
resolution and enhanced quality of life. Biliary obstruction is the most common complication
when a tumour is unresectable or a patient is not suitable for surgery. Options for relieving biliary
obstruction include surgical bypass, endoscopic biliary stenting, and percutaneous biliary drainage.
Surgical biliary bypass is associated with the most procedural-associated morbidity and mortality.
• Tumour palliation can be attempted using photodynamic therapy. A photosensitising agent is
used with an endoscopic laser, resulting in selective tumour death. Radiofrequency ablation,
transcatheter arterial embolisation,[63] and radioembolisation with yttrium 90[64] are also used in
selected centres for tumour palliation.

Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications,
drug interactions, and alternative dosing. ( see Disclaimer )

Acute ( summary )
resectable disease

intrahepatic tumour 1st partial liver resection

adjunct pre-operative portal vein embolisation or

TREATMENT

biliary drainage

adjunct further resection or ablative therapy, or

chemotherapy ± radiotherapy

extrahepatic tumour 1st surgical excision

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Cholangiocarcinoma Treatment

Acute ( summary )
adjunct pre-operative portal vein embolisation or
biliary drainage

adjunct chemotherapy ± radiotherapy

unresectable disease

liver transplant 1st liver transplant

candidate

plus chemotherapy ± radiotherapy

liver transplant non- 1st chemotherapy ± radiotherapy

candidate

1st palliative therapy

TREATMENT

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 Cholangiocarcinoma Treatment

Treatment options

Acute
resectable disease

intrahepatic tumour 1st partial liver resection

» Patients who have resectable tumours have:

» No evidence of metastases, regional lymph

node involvement, portal vein extension, or
bilateral ductal extension

» Imaging indicating the possibility that the

surgeon will be able to resect with clear margins
and be able to clear at least one side of the
biliary tree of tumour

» No comorbidities that prevent them from

undergoing surgery.
adjunct pre-operative portal vein embolisation or
biliary drainage

» Pre-operative portal vein embolisation may

contribute to reduction of complications and
surgery-related mortality, and may be considered
for patients undergoing right hepatectomy or
larger resection, such as trisegmentectomy.[49]
[50] It may also be considered for patients
undergoing hepatectomy with a planned
resection rate exceeding 50% to 60%, especially
those with a jaundiced liver.

» Pre-operative biliary drainage has been used

to reduce morbidity and mortality in patients
with obstructive jaundice. However, there are
several studies that are against the routine
use of pre-operative surgical endoscopic or
percutaneous stenting.[31] [52] [53] Despite
this evidence, pre-operative biliary drainage
remains a controversial procedure, and is still
advocated by several centres.[54] Generally, if
patients have a resectable lesion and surgery
can be done within a few days of diagnosis, this
procedure is not required.

» Pre-operative biliary drainage can be done

using covered or uncovered metallic stents, and
current evidence indicates that covered stents
are better for a longer duration of patency.[55]
TREATMENT

adjunct further resection or ablative therapy, or

chemotherapy ± radiotherapy

» If resection is successful and there is no local

residual disease, patients can be followed up by

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Cholangiocarcinoma Treatment

Acute
observation. There is no adjuvant regimen that is
proven to improve survival.

» If, after resection, there is some residual

disease (i.e., positive margins), it is
recommended that adjunctive therapy
with further resection, ablative therapy, or
chemotherapy with or without radiotherapy is
considered.

» No recommended standard chemotherapy

regimen is currently available. Chemotherapy
is usually an option if negative margins are
not obtained following resection. If negative
margins are obtained, the role of chemotherapy
is controversial.[44]
extrahepatic tumour 1st surgical excision

» Patients who have resectable tumours have:

» No evidence of metastases, regional lymph

node involvement, portal vein extension, or
bilateral ductal extension

» Imaging indicating the possibility that the

surgeon will be able to resect with clear margins
and be able to clear at least one side of the
biliary tree of tumour

» No comorbidities that prevent them from

undergoing surgery.

» For patients with an extrahepatic

cholangiocarcinoma, the type of surgery
depends on the location of the tumour:

» Tumours that are within the proximal third

of the extrahepatic biliary tree should be
removed by hilar resection, partial hepatectomy
combined with caudate lobe resection, and
lymphadenectomy.[45]

» Tumours within the mid-third

undergo major bile duct excision with
lymphadenectomy. Either partial hepatectomy or
pancreaticoduodenectomy may be required to
achieve complete tumour clearance.

» Distal extrahepatic tumours should be

removed with pancreaticoduodenectomy with
lymphadenectomy.
TREATMENT

» Tumours can be resected by portal vein

resection when the portal vein is involved. This
approach confers a marginal benefit over not
undergoing resection.[46]

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 Cholangiocarcinoma Treatment

Acute
adjunct pre-operative portal vein embolisation or
biliary drainage

» Pre-operative portal vein embolisation may

contribute to reduction of complications and
surgery-related mortality, and may be considered
for patients undergoing right hepatectomy or
larger resection, such as trisegmentectomy.[49]
[50] It may also be considered for patients
undergoing hepatectomy with a planned
resection rate exceeding 50% to 60%, especially
those with a jaundiced liver.

» Pre-operative biliary drainage has been used

to reduce morbidity and mortality in patients
with obstructive jaundice. However, there are
several studies that are against the routine
use of pre-operative surgical endoscopic or
percutaneous stenting.[31] [52] [53] Despite
this evidence, pre-operative biliary drainage
remains a controversial procedure, and is still
advocated by several centres.[54] Generally, if
patients have a resectable lesion and surgery
can be done within a few days of diagnosis, this
procedure is not required.

» Pre-operative biliary drainage can be done

using covered or uncovered metallic stents, and
current evidence indicates that covered stents
are better for a longer duration of patency.[55]
adjunct chemotherapy ± radiotherapy

» If the tumour is resected successfully and there

are no positive lymph nodes, the patient has
a choice either to undergo chemotherapy with
radiotherapy or to have no further treatment.

» If resection margins are positive or lymph

nodes are involved, the patient should be
offered chemotherapy,[47] [48] either alone or in
combination with radiotherapy.

» See local specialist protocol for dosing

guidelines of chemotherapeutic agents.
unresectable disease

liver transplant candidate 1st liver transplant

» Most cholangiocarcinomas present as

unresectable. Criteria that make a tumour
TREATMENT

unresectable are:[56]

» Patient factors: comorbidity; co-existent hepatic

cirrhosis.

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Cholangiocarcinoma Treatment

Acute
» Tumour-related factors: tumour extension
to secondary biliary radicles; encasement
or occlusion of main portal vein proximal
to the bifurcation; atrophy of one hepatic
lobe with contralateral portal vein branch
encasement or occlusion; atrophy of one hepatic
lobe with contralateral tumour extension to
secondary biliary radicles; unilateral tumour
extension to secondary biliary radicles with
contralateral portal vein branch encasement or
occlusion; histologically proven metastasis to
regional lymph nodes; lung, liver, or peritoneal
metastasis.

» Results are mixed concerning liver transplant,

but it can be supported in highly selected
groups of patients with unresectable disease.
They include patients with locally advanced
disease (typically hilar) involving the surrounding
large vessels (portal vein, hepatic artery)
and extension to secondary biliary radicles.
Patients with underlying biliary inflammation
(e.g., primary sclerosing cholangitis) or hepatic
dysfunction precluding surgery may also qualify
for liver transplant.[57] [58] [59] Regional lymph
node involvement and the presence of distant
metastasis exclude the patient from transplant.

» Most high-volume centres performing this

procedure use neoadjuvant chemotherapy or
chemoradiotherapy, with the thought that it will
limit recurrence from metastasis and lymphatic
spread.[60] 1[C]Evidence
plus chemotherapy ± radiotherapy

» Most high-volume centres performing liver

transplant use neoadjuvant chemotherapy or
chemoradiotherapy, with the thought that it will
limit recurrence from metastasis and lymphatic
spread.[60] 1[C]Evidence
liver transplant non- 1st chemotherapy ± radiotherapy
candidate
» Most cholangiocarcinomas present as
unresectable. Criteria that make a tumour
unresectable are:[56]

» Patient factors: comorbidity; co-existent hepatic

cirrhosis.

» Tumour-related factors: tumour extension

to secondary biliary radicles; encasement
TREATMENT

or occlusion of main portal vein proximal to

the bifurcation; unilateral tumour extension to
secondary biliary radicles with contralateral
portal vein branch encasement or occlusion;
atrophy of one hepatic lobe with contralateral
portal vein branch encasement or occlusion;

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 Cholangiocarcinoma Treatment

Acute
atrophy of one hepatic lobe with contralateral
tumour extension to secondary biliary
radicles; histologically proven metastasis to
regional lymph nodes; lung, liver, or peritoneal
metastasis.

» Within the group of patients who have

unresectable disease, only a small number
qualify for a liver transplant. They include
patients with locally advanced disease involving
the surrounding large vessels (portal vein,
hepatic artery) and extension to secondary
biliary radicles. Patients with underlying
biliary inflammation (e.g., primary sclerosing
cholangitis) or hepatic dysfunction precluding
surgery may also qualify for liver transplant.[57]
[58] [59]

» Patients who do not meet the above criteria

are offered chemotherapy with gemcitabine plus
a platinum compound,[47] [48] either alone or
in combination with radiotherapy. Due to the
limited response rate in this tumour, treatment is
generally discontinued if progression of disease
is confirmed by imaging.

» See local specialist protocol for dosing

guidelines of chemotherapeutic agents.
1st palliative therapy

» The alternative option for unresectable

tumours is palliative care. The goal of palliation
is symptom resolution and enhanced quality
of life. Biliary obstruction is the most common
complication when a tumour is unresectable
or a patient is not suitable for surgery. Options
for relieving biliary obstruction include surgical
bypass, endoscopic biliary stenting, and
percutaneous biliary drainage. Surgical biliary
bypass is associated with the most procedural-
associated morbidity and mortality.

» Tumour palliation can be attempted using

photodynamic therapy. A photosensitising agent
is used with an endoscopic laser, resulting in
selective tumour death. Radiofrequency ablation,
transcatheter arterial embolisation,[63] and
radioembolisation with yttrium 90[64] are also
used in selected centres for tumour palliation.
TREATMENT

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Cholangiocarcinoma Treatment

Emerging
Duodenoscope-assisted cholangioscopy
Experimental diagnostic procedure that is also being trialled for stent placement.[65]

TREATMENT

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 Cholangiocarcinoma Follow up

Recommendations
Monitoring
FOLLOW UP

After surgical resection, imaging (CT, MRI) every 3 to 6 months is recommended, with increasing
intervals over time; LFTs should also be performed to exclude recurring obstruction. Recurrent hilar
cholangiocarcinoma is unlikely to be resectable; if the recurrence is peripheral, then resection or ablation
therapy may be options.

Patient instructions

Complications

Complications Timeframe Likelihood

cholangitis short term low

More common in previously instrumented or obstructed biliary systems; treated with antibiotics and biliary
drainage.

biliary leak (surgical complication) short term low

Biliary leaks can occur in approximately 5% to 10% of complex bile duct anastomoses.

biliary obstruction variable medium

Tumour overgrowth obstructing the biliary tree and requiring repeat resection, surgical bypass, or biliary
stenting (percutaneous).

Prognosis

Node-positive cholangiocarcinoma is a poor prognostic indicator of survival. Metastatic disease precludes

resection and has a poor prognosis. The common early pattern of spread is to regional lymph nodes and to
distant sites in the liver.

The 5-year survival for surgical resection alone ranges from 20% to 43%.[40] [41] [42] [43] For surgical
resection with chemotherapy, the 5-year survival rate is 26%. The response rate to chemotherapy alone is
<15%.[66] For liver transplant, there is a recurrence rate of 51% within 2 years of the procedure.[67]

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Cholangiocarcinoma Guidelines

Diagnostic guidelines

Europe

Biliary cancer: ESMO clinical practice guidelines

Published by: The European Society for Medical Oncology Last published: 2016

Guidelines for the diagnosis and management of intrahepatic

cholangiocarcinoma
Published by: European Association for the Study of the Liver Last published: 2014

Guidelines for the diagnosis and treatment of cholangiocarcinoma: an

update
Published by: British Association for the Study of the Liver; British Last published: 2012
Society of Gastroenterology

GUIDELINES
North America

NCCN clinical practice guidelines in oncology: hepatobiliary cancers

Published by: National Comprehensive Cancer Network Last published: 2017

Treatment guidelines

Europe

Biliary cancer: ESMO clinical practice guidelines

Published by: The European Society for Medical Oncology Last published: 2016

Guidelines for the diagnosis and management of intrahepatic

cholangiocarcinoma
Published by: European Association for the Study of the Liver Last published: 2014

Guidelines for the diagnosis and treatment of cholangiocarcinoma: an

update
Published by: British Association for the Study of the Liver; British Last published: 2012
Society of Gastroenterology

North America

NCCN clinical practice guidelines in oncology: hepatobiliary cancers

Published by: National Comprehensive Cancer Network Last published: 2017

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 Cholangiocarcinoma Evidence scores

Evidence scores
1. Post-liver transplant survival rates: there is poor-quality evidence, from a small Mayo Clinic pilot cohort
study published in 2000, for very encouraging 1-, 3-, and 5-year post-transplant survival rates with
neoadjuvant chemoradiation (92%, 82%, and 82%, respectively), but these results have not been
repeated since.[61]
Evidence level C: Poor quality observational (cohort) studies or methodologically flawed randomized
controlled trials (RCTs) of <200 participants.
EVIDENCE SCORES

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Cholangiocarcinoma References

Key articles
• American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York, NY: Springer-

REFERENCES
Verlag; 2010.

• Khan SA, Davidson BR, Goldin RD, et al; British Society of Gastroenterology. Guidelines for the
diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657-1669. Full text
Abstract

• Lan BY, Kwee SA, Wong LL. Positron emission tomography in hepatobiliary and pancreatic
malignancies: a review. Am J Surg. 2012;204:232-241. Abstract

• Valle JW, Furuse J, Jitlal M, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-
analysis of two randomised trials. Ann Oncol. 2014;25:391-398. Abstract

References
1. Bridgewater J, Galle PR, Khan SA, et al; European Association for the Study of the Liver.
Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol.
2014;60:1268-1289. Full text Abstract

2. American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York, NY: Springer-
Verlag; 2010.

3. Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J
Hepatol. 2006;45:856-867. Abstract

4. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer.
1995;75:171-190. Abstract

5. Levin B. Gallbladder carcinoma. Ann Oncol. 1999;10(suppl 4):129-130. Abstract

6. Pitt HA, Dooley WC, Yeo CJ, et al. Malignancies of the biliary tree. Curr Probl Surg. 1995;32:1-90.
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7. Shin HR, Lee CU, Park HJ, et al. Hepatitis B and C virus, Clonorchis sinensis for the risk of liver
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35. Farrell RJ, Agarwal B, Brandwein SL, et al. Intraductal US is a useful adjunct to ERCP for
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37. Magnuson TH, Bender JS, Duncan MD, et al. Utility of magnetic resonance cholangiography in the
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38. Wiersema MJ, Vilmann P, Giovannini M, et al. Endosonography-guided fine-needle aspiration biopsy:
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of the topics can be found on bestpractice.bmj.com . Use of this content is
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34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 19, 2017.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
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66. Furuse J, Okusaka T, Funakoshi A, et al. Early phase II study of uracil-tegafur plus doxorubicin in
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This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 19, 2017.
BMJ Best Practice topics are regularly updated and the most recent version
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of the topics can be found on bestpractice.bmj.com . Use of this content is
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 Cholangiocarcinoma Images

Images
IMAGES

Figure 1: Gallbladder ultrasound of mass (arrows)

From the collection of Dr Joseph Espat; used with permission

36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 19, 2017.
BMJ Best Practice topics are regularly updated and the most recent version
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Cholangiocarcinoma Images

IMAGES
Figure 2: ERCP image of hilar cholangiocarcinoma: Klatskin's tumour with stricture of duct bifurcation
(arrows)
From the collection of Dr Joseph Espat; used with permission

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BMJ Best Practice topics are regularly updated and the most recent version
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IMAGES Cholangiocarcinoma Images

Figure 3: ERCP image of hepatic duct cholangiocarcinoma with duct stricture (arrows)
From the collection of Dr Joseph Espat; used with permission

38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Dec 19, 2017.
BMJ Best Practice topics are regularly updated and the most recent version
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Cholangiocarcinoma Disclaimer

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Contributors:

// Authors:

N. Joseph Espat, MD, MS, FACS

Chairman of Surgery
Professor and Chief Surgical Oncology, Director Cancer Center, Department of Surgery, Roger Williams
Medical Center, Boston University School of Medicine, Providence, RI
DISCLOSURES: NJE has taught faculty courses for Medtronic and Sirtex.

Ponnandai Somasundar, MD, MPH, FACS

Associate Professor and Associate Chief
Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Boston University School of
Medicine, Providence, RI
DISCLOSURES: PS declares that he has no competing interests.

// Peer Reviewers:

Kevin Watkins, MD
Assistant Professor
Department of Surgery, Health Science Center, SUNY, Stony Brook, NY
DISCLOSURES: KW declares that he has no competing interests.

Savio Reddymasu, MD
GI Fellow
Department of Medicine, Center for Gastrointestinal Motility, Division of Gastroenterology and Hepatology,
University of Kansas Medical Center, Kansas City, KS
DISCLOSURES: SR declares that he has no competing interests.

Satvinder Mudan, MBBS, BSc, MD, FRCS

Consultant in Surgical Oncology
The Royal Marsden Hospital, London, UK
DISCLOSURES: SM declares that he has no competing interests.