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Chapter 13
common hepatic duct below the biliary confluence,
type II involve the biliary confluence, type IIIa
involve the biliary confluence extending into the
right hepatic duct, type IIIb involve the biliary
confluence extending into the left hepatic duct and
type IV involve the confluence and extend into both
the left and right hepatic ducts.
The vast majority of cholangiocarcinomas are
adenocarcinoma, whereas other histologic variants
comprise 5%.
3
A small number show different
patterns with focal areas of papillary carcinoma
with mucous production, signet-ring cells, squamous
cell, mucoepidermoid and spindle cell variants.
20,21
The Liver Cancer Study group of Japan established
a subclassification of these tumours based on
morphology: (1) mass-forming type; (2) periductalinfiltrating type; (3) intraductal growth type.
20
Periductal infiltrating is the most common, and
as the name suggests, is associated with infiltrative
characteristics while also causing fibrosis of periductal
tissues and annular bile duct thickening.
consequence, a non-diagnostic preoperative biopsy
is not uncommon.
21
Although outside the scope of
3,20,21
As a
this review, tumours with both hepatocellular and
cholangiocellular differentiation (combined tumours)
are rare but well described. Their clinical behaviour
more closely resembles that of cholangiocarcinoma
than hepatocellular carcinoma, and they tend to
display aggressive biology.
22
Three macroscopic subtypes of extrahepatic
cholangiocarcinoma are described: sclerosing,
nodular and papillary, of which the first two
are often combined into one (i.e. nodularsclerosing) since features of both types are often
seen together.
23
Papillary tumours represent a
less common morphological variant, accounting
for approximately 10% of tumours arising from
the extrahepatic biliary tree.
23
Papillary tumours
are soft and friable, may be associated with little
transmural invasion, and are characterised by a
mass that expands rather than contracts the duct
Fig.13.1). Although papillary tumours may grow to
(
significant size, they often arise from a well-defined
stalk, with the bulk of the tumour mobile within the
ductal lumen. Despite this histological variant being
the minority of cases, recognition of this entity is
important since they are more often resectable
and have a more favourable prognosis than their
histological counterparts.
24
Tumours of the lower bile duct, namely midand distal bile duct, are classified according to
their anatomical location, although there may be
considerable overlap. Mid-bile duct tumours arise
between the upper border of the duodenum and the
cystic duct, while distal bile duct tumours arise from
the duodenum to the ampulla of Vater. Tumours of
the distal bile duct represent approximately 5–10%
of all periampullary tumours.
17
True mid-duct
tumours are distinctly uncommon, and thus Nakeeb
et al. have proposed an alternative classification
scheme that divides cholangiocarcinomas into
intrahepatic, perihilar and distal subgroups,
thereby eliminating the mid-duct group, which is
often difficult to classify accurately.
17
As is true
throughout the biliary tree, adenocarcinoma is the
principal histological type in the lower bile duct, and
it has previously been suggested that the papillary
variant is more common at this location compared
to the biliary confluence.
24
Clinical presentation
The clinical presentation of cholangiocarcinoma
is directly determined by the location/level of
biliary involvement. Patients with extrahepatic
cholangiocarcinoma may present earlier due to
outflow obstruction of the biliary tree. Therefore,
these patients can present with the classic signs
and symptoms of hyperbilirubinaemia (painless
jaundice, pruritus, pale stool and dark urine).
The clinical presentation of distal bile duct cancer
is generally indistinguishable from that of hilar
cholangiocarcinoma or other periampullary
malignancies. Progressive jaundice is seen in
75–90% of patients, with serum bilirubin
levels often exceeding 10 mg/dL.25 Distal bile
duct tumours are frequently mistaken for
adenocarcinoma of the pancreas, the most
common periampullary malignancy. Of note,
patients with papillary tumours may give a history
of intermittent jaundice, perhaps due to the ballvalve effect of a pedunculated mass within the
lumen or, more likely, small fragments of tumour
having passed into the common bile duct.
In stark contrast, intrahepatic cholangiocarcinoma
patients are typically asymptomatic. In the
majority of cases, early symptoms are nebulous
(weight loss, abdominal discomfort) and many
are identified incidentally on cross-sectional
imaging or following the discovery of abnormal
liver function tests. In patients with no previous
biliary intervention, cholangitis is rare at initial
presentation. Occasionally, patients with longstanding biliary obstruction and/or portal vein
involvement may present with symptoms related to
portal hypertension. Additionally, in those with PSC,
distal ductal or periductal lesions can be difficult to
differentiate from benign biliary strictures.
3
Diagnostic assessment
Radiological investigation
Preoperative staging should be aimed not
only at the exclusion of distant metastases but
222
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Malignant lesions of the biliary tract
a
c
Figure13.1 • Gross and cholangiographic appearance of a papillary cholangiocarcinoma (a, c) and a nodular-
sclerosing tumour (b, d). In (a) and (c), note that the papillary tumour occupies the lumen and expands the duct (black
arrow). A biliary stent is visualised (white arrow). In (b) and (d), the nodular-sclerosing variant constricts the lumen, nearly
obliterating it (white arrow).
Reproduced with permission from Blumgart LH, editor. Surgery of the liver, biliary tract, and pancreas. 4th ed. Elsevier
Saunders; 2006.
b
d
also the assessment of local extent of disease.
Cross-sectional, contrast-enhanced imaging is the
mainstay of investigation. Multiphasic computed
tomography (CT) of the chest, abdomen and pelvis
to include portal venous and arterial phases should
be used to assess the extent of disease in the liver and
porta hepatis while also evaluating for metastatic
disease. Imaging should include thin cuts to
elucidate detailed relationships between the tumour
and porta hepatis structures. It should be noted that
initial imaging studies should be performed prior to
biliary stenting (if it is to be performed), as stenting
will cause local inflammation, making assessment of
tumour extent difficult.
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Computed tomography
Cross-sectional imaging provided by CT remains
an important study for evaluating patients with
biliary obstruction and can provide valuable
information regarding the level of obstruction,
vascular involvement and liver atrophy. As portal
venous inflow and bile flow are important in the
maintenance of liver cell size and mass, segmental
or lobar atrophy may be evident on CT that would
suggest portal venous occlusion or, alternatively,
long-standing biliary obstruction in the absence of
portal venous involvement.
26
Generally speaking,
CT offers excellent assessment of the radial extent
of soft-tissue involvement, direct liver invasion
223
Chapter 13
Figure13.2 • Characteristic CT appearance of
intrahepatic cholangiocarcinoma demonstrating
heterogeneous enhancement.
of perihilar lesions and the relationship to portal
structures. For instance, dilated intrahepatic ducts
with a normal or collapsed gallbladder allude to a
perihilar cholangiocarcinoma, particularly if there
is any evidence of a soft-tissue mass. Whereas a
distended gallbladder with normal intrahepatic ducts
alludes to either stone disease or tumour obstructing
the cystic duct, and a distended gallbladder with
dilated intra- and extrahepatic ducts suggests either
choledocholithiasis or a distal biliary malignancy.
On contrast-enhanced CT, variable rim-like
enhancement can be observed, predominantly on
the arterial phase images with gradual centripetal
enhancement on delayed imaging (
Fig.13.2).
Current CT imaging has been found to identify
cholangiocarcinoma in 94–100% of patients
and the positive and negative predictive values
for determining resectability are 92% and 85%,
respectively.
27–29
However, CT imaging tends to
underestimate the proximal extent of tumour within
the bile duct and is thus not ideal as the primary
determinant of resectability.
30
In fact, reported
accuracy for detecting the longitudinal spread along
bile ducts is 81% as compared to an accuracy of
100% for detecting radial spread into adjacent
structures.
lymph node metastases, since CT has a documented
sensitivity ranging from 35% to 65%.
31
Another limitation is the detection of
31
Duplex ultrasonography
Ultrasonography is a non-invasive, but operatordependent, study that often precisely delineates the
level of the tumour within the bile duct (
Fig.13.3).
It can also provide information regarding tumour
extension within the bile duct and in the periductal
32
tissues.
In a series of 19 consecutive patients with
malignant hilar obstruction, ultrasonography with
colour spectral Doppler technique was equivalent
3
Figure13.3 • Ultrasonographic view of a hilar
cholangiocarcinoma showing a papillary tumour (m)
extending into the right anterior (a) and posterior (p)
sectoral ducts and the origin of the left duct (l). The
adjacent portal vein (v) is not involved and has normal flow.
Reproduced with permission from Blumgart LH, editor.
Surgery of the liver, biliary tract, and pancreas., 4th ed.
Elsevier Saunders; 2006.
to angiography and CT portography in diagnosing
lobar atrophy, level of biliary obstruction, hepatic
parenchymal involvement and venous invasion.
32
Duplex ultrasonography is particularly useful
for assessing portal venous invasion. In a series
of 63 consecutive patients from the Memorial
Sloan-Kettering Cancer Center (MSKCC), duplex
ultrasonography predicted portal vein involvement
in 93% of cases, with a specificity of 99% and a
97% positive predictive value. In the same series,
angiography with CT angio-portography had 90%
sensitivity, 99% specificity and a 95% positive
predictive value.
33
Magnetic resonance cholangiopancreatography
(MRCP)
Several studies have demonstrated the utility of
magnetic resonance cholangiopancreatography
(MRCP) in evaluating patients with biliary
obstruction, and it has now become the imaging
modality of choice.
34,35
MRCP may not only identify
the tumour and the level of biliary obstruction, but
may also reveal obstructed and isolated ducts not
appreciated at endoscopic or percutaneous study. By
virtue of being an axial imaging modality, MRCP has
further advantages over standard cholangiography
by also providing information regarding the patency
of hilar vascular structures, the presence of nodal
or distant metastases, the presence of lobar atrophy
hepatic parenchymal involvement or metastatic
224
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Malignant lesions of the biliary tract
Figure13.4 • Cross-sectional MRCP from a patient with
hilar cholangiocarcinoma extending into the left hepatic
duct and left lobe atrophy. The bile ducts appear white.
The left lobe is small with dilated and crowded ducts
(arrowhead). The principal caudate lobe duct, seen joining
the left hepatic duct, is also dilated (arrow).
Reproduced with permission from Blumgart LH, editor.
Surgery of the liver, biliary tract, and pancreas. 4th ed.
Elsevier Saunders; 2006.
hepatic disease (Fig.13.4). As compared to invasive
cholangiopancreatography, MRCP has comparable
rates of detecting the location and extent of tumour
within the biliary tree.
27,36
Furthermore, because
it does not require biliary intubation, it is not
associated with the same incidence of bacterobilia
and infectious complications that is frequently
associated with standard cholangiography.
37
In general, cholangiocarcinoma is hypointense
on T1-weighted images and hyperintense on T2weighted imaging.
3
These lesions demonstrate initial
rim enhancement characterised by progressive
and concentric enhancement post-administration
of contrast material. Generally, the lesions do not
completely enhance post-contrast. In the absence of
a separate primary source of disease, a lesion in the
liver with this morphology on magnetic resonance
imaging (MRI) evaluation can be considered
virtually diagnostic of cholangiocarcinoma without
a tissue diagnosis. Intrahepatic cholangiocarcinomas
may only enhance completely on delayed imaging
obtained hours after contrast administration, a
finding related to the desmoplastic nature of the
tumour. Capsular retraction may also be seen.
38,39
Additionally, magnetic resonance
cholangiopancreaticography (MRCP) can more
accurately evaluate biliary ducts proximal to a lesion
that may not be adequately filled with contrast during
endoscopic retrograde cholangiopancreatography
(ERCP), since the MRI provides biliary imaging
above and below the obstruction.
accuracy in determining the extent of bile duct
involvement is 71–96%.
3
In fact, reported
40,41
That being said,
MRCP has limitations, in that it will understage up
to 20% of perihilar cases, can overstage patients
with indwelling biliary stents and is overly sensitive
to motion.
3
Positron emission tomography
Traditional fluorodeoxyglucose positron emission
tomography (FDG-PET) imaging may have
benefit in the assessment of cholangiocarcinoma.
In one prospective series comparing patients with
cholangiocarcinoma to those with benign biliary
disease, PET imaging diagnosed cholangiocarcinoma
with a sensitivity of 92% and a specificity of 93%.
42
Additionally, with respect to the assessment of
metastatic nodal disease, PET was found to have a
specificity of 100%, compared to CT which had a
specificity of 59%.
43
Moreover, it has been reported
that FDG-PET imaging has altered surgical treatment
plans in up to 30% of patients by identifying occult
distant metastatic disease and also proving findings
suspicious on CT to be negative.
44,45
In the authors'
experience with FDG-PET for all biliary tract cancer,
the information provided influenced management
in 24% of patients.
46
However, false-positive
findings are common, specifically in patients with
indwelling biliary stents. Although the evidence
is limited to small reviews, PET imaging should
be considered when evaluating newly diagnosed
biliary malignancies, not only to evaluate for
distant metastatic disease but also to confirm/refute
questionable findings on cross-sectional imaging.
Invasive modalities
Direct cholangiography
Although ERCP may provide helpful information,
percutaneous transhepatic cholangiography (PTC)
displays the intrahepatic bile ducts more reliably.
Moreover, PTC may be required in patients with
an obstructive perihilar lesion. Unlike diagnostic
radiographic imaging modalities, PTC offers the
ability to obtain tissue for sampling (brushing,
biopsy) and also to place a biliary stent to relieve
symptoms of obstructive jaundice.
Endoscopy
In cases of biliary dilatation without an obvious
mass lesion seen on cross-sectional imaging,
endoscopic modalities (endoscopic ultrasound
[EUS] and ERCP) offer the ability to further
characterise indeterminate biliary strictures, assess
for the presence of a biliary ductal mass, assist with
staging by identifying lymphadenopathy or liver
lesions and perform biliary stenting.
Cytology
Pathology results obtained through brushings
during PTC or endoscopy must be interpreted with
great caution since sensitivities for brush cytology
for diagnosing cholangiocarcinoma range from
30% to 60%.
47,48
A postulation for this low yield
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225
Chapter 13
is the dense fibroplastic reaction observed with
cholangiocarcinoma. This relatively low yield, in
combination with the lack of standardised criteria
for cytologic evaluation and reporting, continue to
limit the usefulness of this modality.
3
In an attempt to improve these results, advanced
cytology techniques to detect aneuploidy (fluorescence
in situ hybridisation [FISH] using fluorescent probes
to detect chromosomal amplification and digital
image analysis that quantifies nuclear DNA as
a ratio of normal ploidy) have been studied.
49,50
Preliminary results have found that when used in
combination with routine cytology, the sensitivity
may increase without compromising the specificity
for diagnosing cholangiocarcinoma.
50
Choledochoscopy
Endoscopic choledochoscopy utilises a narrowcalibre fibreoptic choledochoscope passed through
the working channel of a standard duodenoscope.
It can be used to directly observe luminal
filling abnormalities noted on MRCP or direct
cholangiography. Malignant biliary strictures can
be identified by the presence of dilated or tortuous
vessels, mucosal ulceration, polypoid or nodular
masses, or villous mucosal morphology.
51,52
Endoscopic choledochoscopy allows for passage
across strictures to second-order and third-order bile
ducts, making it particularly useful in patients with
PSC, when it can be used to locate and directly biopsy
a dominant stricture.
3
With respect to diagnosis,
the combination of endoscopic choledochoscopy
with ERCP and tissue sampling has been reported
to increase the sensitivity for the detection of
malignancy in patients with indeterminate biliary
strictures from 58% to 100%.
53
SpyGlass endoscopy
SpyGlass may overcome some limitations of
conventional cholangioscopy. A recent prospective
analysis of a cohort of patients with indeterminate
biliary lesions following ERCP was performed.
Fifty-two patients underwent SpyGlass and targeted
biopsies and a definite diagnosis was made in 94% of
cases. A concordance rate of 90% was found between
SpyGlass biopsy results and surgical pathology
specimens. The sensitivity, specificity, and positive
and negative predictive values were 88%, 94%, 96%
and 85%, respectively. Overall, SpyGlass allowed
adequate biopsy sampling and definite diagnosis
in the vast majority of patients with indeterminate
biliary lesions.
54
Although a paucity of data remains,
this technology may prove beneficial.
Serum markers
CA 19-9 and carcinoembryonic antigen (CEA)
levels may be elevated. Unfortunately, these markers
can also be elevated in patients with cholestasis,
hepatic parenchymal injury, benign biliary
obstruction and gastric, pancreatic, colorectal and
gynaecological cancers. However, serum markers
may prove beneficial in certain circumstances; for
instance, CA 19-9 levels >
cholangiocarcinoma in patients without PSC have a
sensitivity of 53%.
55,56
the sensitivity of CA 19-9 ranges from 38% to
89%, with a specificity of 50–98%.
100 U/mL in diagnosing
In those with PSC, however,
55,56
Although
the diagnostic accuracy of CA 19-9 in patients
with cholangiocarcinoma is variable, an extremely
elevated level may be indicative of unresectable or
metastatic disease.
3
Staging
Hilar cholangiocarcinoma
The staging systems currently used for hilar
cholangiocarcinoma do not account fully for all
of the tumour-related variables that influence
resectability, namely biliary tumour extent,
lobar atrophy and vascular involvement. The
modified Bismuth–Corlette classification stratifies
patients solely based on the extent of biliary duct
involvement by tumour.
some extent, it is not indicative of resectability
or survival. Similarly, the earlier American Joint
Committee on Cancer (AJCC) T-stage system (6th
edition) was based largely on pathological criteria
and had little applicability for preoperative staging.
The ideal staging system should accurately predict
resectability and the likelihood of associated
metastatic disease, and also correlate with survival.
The authors have proposed such a preoperative
staging system (Blumgart Clinical Staging
System).
of portal venous involvement and lobar atrophy into
the proper context for determining resectability,
especially when partial hepatectomy is an important
component of the operative approach (Table13.1).
58,59
This staging system places the finding
Specifically, the MSKCC system stratifies the extent
of disease based on four factors: (1) involvement
of the biliary confluence; (2) second-order biliary
radical involvement; (3) portal vein involvement;
(4) hepatic lobar atrophy. Based upon these factors,
a clinical T stage is determined.
tumour with unilateral extension into second-order
bile ducts that is associated with ipsilateral portal
vein involvement and/or lobar atrophy would
still be considered potentially resectable, while
such involvement on the contralateral side would
preclude a resection. The authors initially found that
this staging system correlated well with resectability,
57
Although useful to
59
For example, a
226
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Malignant lesions of the biliary tract
Table13.1 • Proposed T-stage criteria for hilar
cholangiocarcinoma
Stage Criteria
T1
Tumour involving biliary confluence ± unilateral
extension to second-order biliary radicles
T2
Tumour involving biliary confluence ± unilateral
extension to second-order biliary radicles
AND ipsilateral portal vein
involvement ± ipsilateral hepatic lobar atrophy
T3
Tumour involving biliary confluence + bilateral
extension to second-order biliary radicles
OR unilateral extension to second-order
biliary radicles with contralateral portal vein
involvement
OR unilateral extension to second-order biliary
radicles with contralateral hepatic lobar atrophy
OR main or bilateral portal venous involvement
Reproduced with permission from Jarnagin WR, Fong Y,
DeMatteo RP, etal. Staging, resectability, and outcome
in 225 patients with hilar cholangiocarcinoma. Ann Surg
2001;234:507–19.
the likelihood of associated distant metastatic
disease, and median survival (Table13.2).
Box13.1 • Criteria of unresectability
Patient factors
Medically unfit or otherwise unable to tolerate a major
operation
Hepatic cirrhosis
Local tumour-related factors
Tumour extension to secondary biliary radicles bilaterally
Encasement or occlusion of the main portal vein proximal to
its 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
Metastatic disease
Histologically proven metastases to distant lymph node
basins*
Lung, liver or peritoneal metastases
*Includes peripancreatic, periduodenal, coeliac, superior
mesenteric or posterior pancreatico-duodenal lymph nodes.
Reproduced with permission from Jarnagin WR, Fong Y,
DeMatteo RP, etal. Staging, resectability, and outcome
in 225 patients with hilar cholangiocarcinoma. Ann Surg
2001;234:507–19.
Independent confirmation of the utility of the
Blumgart Clinical Staging System was recently
reported in a series of 85 patients from China as well
as 380 patients from MSKCC where the preoperative
clinical T-staging system predicted resectability
(P < 0.001), metastatic disease (P <0.001) and R0
resection (P = 0.007).
59,60
system is of limited clinical use, as it is based on
pathological information and does not provide
any information pertaining to factors that define
resectability. The most important of these is the
presence of tumour involvement of the portal
vein, superior mesenteric artery or common
The authors' criteria for unresectability are
detailed in Box 13.1. This staging scheme is now
incorporated in the 7th edition (2009) of the AJCC
staging system for hilar cholangiocarcinoma.
hepatic artery. Tumours involving a short segment
of the portal vein (<
2 cm) may be resected with
reconstruction of the vein. Metastatic disease
to distant sites, such as the liver or peritoneum,
represents an absolute contraindication to
Extrahepatic cholangiocarcinoma
Carcinomas of the distal common bile duct are
staged according to the AJCC system (7th edition)
for tumours of the extrahepatic bile ducts. This
Table13.2 • Resectability, incidence of metastatic disease and survival stratified by T stage
Explored
T stage n
with curative
intent Resected
Negative
margins
proceeding with resection; however, involvement of
regional lymph nodes should perhaps be viewed as
a relative contraindication, given the poor survival
in patients with node-positive disease.
Hepatic
resection
Portal
vein
resection
Metastatic
disease
Median
survival
(mth)
1 87 73 (84%) 51 (59%) 38 33 2 18 (21%) 20
2 95 79 (83%) 29 (31%) 24 29 7 40 (43%) 13
3 37 8 (22%) 0 0 0 0 15 (41%) 8
Total 219 160 (71%) 80 (37%) 62 62 9 73 (33%) 16
Reproduced with permission from Jarnagin WR, Fong Y, DeMatteo RP etal. Staging, resectability, and outcome in 225 patients with
hilar cholangiocarcinoma. Ann Surg 2001234:507–19.
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227
Chapter 13
Intrahepatic cholangiocarcinoma
Currently, there is no useful consensus regarding
a clinical staging system for intrahepatic
cholangiocarcinoma. The AJCC TNM classification
for primary liver cancers is applied both to
hepatocellular carcinoma and intrahepatic
cholangiocarcinoma, but is of little clinical value.
Because intrahepatic cholangiocarcinomas tend to
be relatively silent lesions, they are often large at
presentation. Thirty per cent of patients will have
peritoneal or hepatic metastases at presentation
and many of these will not be detected until staging
laparoscopy or exploratory laparotomy is performed.
Management
Preoperative tissue diagnosis
In the authors' view, histological confirmation of
malignancy is not mandatory prior to exploration.
With no prior suggestive history (i.e. prior biliary
tract operation, PSC, hepatolithiasis), the finding
of a focal stenotic lesion combined with the
appropriate clinical presentation is sufficient for
a presumptive diagnosis of intrahepatic or hilar
cholangiocarcinoma.
on a negative result from a needle biopsy or biliary
brush cytology, since they are often misleading,
particularly in the face of compelling radiographic
evidence of malignant disease.
a stricture of the distal bile duct and a clinical
presentation consistent with cholangiocarcinoma (or
any other periampullary malignancy), histological
confirmation of malignancy is also generally
unnecessary, unless non-operative therapy is planned.
Benign strictures do occur in the lower bile duct, but
these are difficult to differentiate definitively from
malignant strictures without resection.
Preoperative biliary drainage
Although patients with lesions suspicious for
cholangiocarcinoma who meet resection criteria
should be taken for an upfront resection, there
are certain situations in which biliary stenting is
necessary.
While the use of routine preoperative drainage
remains controversial, several studies have
reported that the treatment of hyperbilirubinaemia
is associated with decreased postoperative
complications; there has not, however, been a
documented improvement in mortality or survival.
Proponents argue that stenting improves hepatic
function and nutritional status, and reduces the risk
of cholangitis and postoperative liver failure.
Specifically, Kennedy et al. found preoperative
biliary drainage to be associated with improved
perioperative outcomes in patients with a predicted
future liver remnant (FLR) <30%.
61
It is dangerous to rely entirely
62
In patients with
63
Similarly,
on an assessment of 287 consecutive patients
undergoing major liver resection for perihilar
cholangiocarcinoma, incomplete drainage of the
future liver remnant in patients with FLR volume
<50% predicted postoperative mortality.
64
However, in a multicentre, retrospective study,
preoperative biliary drainage did not result in
improved postoperative outcomes in patients
undergoing major surgical resection for perihilar
cholangiocarcinoma. That being said, on a subset
analysis in patients requiring right hepatectomy,
there was an association with decreased mortality
due to liver failure.
65
On the other hand, opponents
believe preoperative drainage increases the risk
of tumour seeding, cholangitis, perioperative
infectious complications and lengthens overall and
postoperative stay.
3
Of note, the median patency of metallic
endoprostheses placed at the biliary confluence is
approximately 6 months, which is significantly
lower than that reported for similar stents placed in
the distal bile duct.
66
Becker etal. reported 1-year
patency rates of 46% and 89% for Wallstents
placed at the biliary confluence and the distal bile
duct, respectively.
67
Due to this higher occlusion
rate, 25% of patients will require re-intervention.
This concurs with our findings of a mean patency
of 6.1 months in 35 patients palliated for malignant
high biliary obstruction by placement of expandable
metallic endoprostheses. The periprocedural
mortality was 14% at 30days, and seven patients
(24%) had documented stent occlusion requiring
repeated intervention.
66
Additionally, hilar tumours frequently involve all
three major hilar ducts (left hepatic, right anterior
sectoral hepatic and right posterior sectoral hepatic),
and thus may require two or more stents for adequate
drainage. That being said, a randomised clinical trial
assessed bilateral and unilateral stent placement
and found unilateral stenting to be associated with
higher rates of successful drainage (87% vs 77%,
= 0.041), lower complications (19% vs 27%,
P
P = 0.026) and lower rates of cholangitis (9% vs
17%, P = 0.013). There was no significant difference
between the two groups with regard to procedurerelated mortality, 30-day mortality, complications
and median survival.
Biliary decompression of an atrophic lobe does
not typically provide much benefit in terms of
lowering serum bilirubin or improving hepatic
function, and should only be performed if necessary
to treat cholangitis.
68
As alluded to above, endoscopic or percutaneous
instrumentation significantly increases the incidence
of bacterial contamination and the subsequent
228
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Malignant lesions of the biliary tract
risk of clinical infection. In fact, the incidence of
bacterobilia approaches 100% after endoscopic
biliary intubation, thus making cholangitis more
common.
37
The presence of overt or subclinical
infection at the time of surgery is a major source
of postoperative morbidity and mortality. Thus,
endoscopic and percutaneous intubations are both
associated with greater morbidity and mortality
following surgical resection or palliative bypass
for hilar cholangiocarcinoma. In an analysis of 71
patients who underwent either resection or palliative
biliary bypass for proximal cholangiocarcinoma, all
patients stented endoscopically and 62% of those
stented percutaneously had bacterobilia. Moreover,
postoperative infectious complications were
doubled in those patients stented before operation
compared to their non-stented counterparts. Of note,
non-infectious complications were equal in both
37
groups.
Enterococcus, Klebsiella, Escherichia coli,
Streptococcus viridans and Enterobacter aerogenes
are the most common organisms, and this spectrum
of bacteria must be considered when administering
perioperative antibiotics. It is imperative to take
intraoperative bile specimens for culture in order to
guide selection of postoperative antibiotic therapy.
Neoadjuvant therapy
To date, there remains a paucity of data on the
efficacy of neoadjuvant therapy in patients with
resectable disease. However, questions have been
raised regarding potential benefits in down-staging
locally advanced hilar disease, although its utility
remains unproven. One meta-analysis has suggested
that systemic therapy, in properly selected patients,
may help achieve an R0 resection and improve
survival.
using chemotherapy alone for down-staging locally
advanced hilar tumours prior to surgical resection are
scarce. The likelihood of achieving meaningful local
tumour response with systemic chemotherapy alone
is low and most neoadjuvant therapy regimens are
combinations of chemotherapy along with radiation.
neoadjuvant therapy in resectable disease.
However, one small series encompassing 40
patients who underwent resection for extrahepatic
cholangiocarcinoma retrospectively evaluated
the use of neoadjuvant chemoradiotherapy. A
pathological complete response was observed in
3/9 (33%) patients. On an assessment of margins,
100% of the preoperative chemoradiotherapy
group had a margin-negative resection compared to
54% for the group who did not receive preoperative
chemoradiotherapy (P <0.01).
of 45 patients with extrahepatic cholangiocarcinoma,
12 received neoadjuvant chemoradiotherapy and
were compared to an adjuvant chemoradiotherapy
group. In the neoadjuvant setting, three had a
69
However, adequate prospective data on
70
Furthermore, there are even fewer data regarding
71
Moreover, in a series
complete pathological response and 11 were able to
undergo a complete (R0) resection. Despite having
more advanced disease at presentation, patients
who received neoadjuvant chemoradiotherapy
had longer 5-year survival rates compared to
their adjuvant counterparts (53 vs 23 months,
respectively).
72
Lastly, one retrospective review recently assessed
neoadjuvant and adjuvant therapy in resectable
biliary tract malignancies. Of 94 patients who
underwent resection for cholangiocarcinoma, 18%
received neoadjuvant chemotherapy. Neoadjuvant
therapy was found to delay resection by an average
of 7months (P <0.0001) and was associated with
inferior median overall survival outcomes compared
to those who underwent upfront resection
(42 months vs 54 months; P = 0.01).73 These trials
are presented as hypothesis-generating and allude to
the need for randomised trials testing this strategy.
Portal vein embolisation
Currently, it remains common practice to consider
portal vein embolisation (PVE) in patients who have
an estimated/anticipated FLR <20–30% of the total
liver volume. Additionally, in patients with underlying
liver dysfunction, or those who have been heavily pretreated with systemic therapy, a FLR <40% may be
used as the cutoff to consider PVE.
3
Traditionally, it
has been used more often in the setting of an extended
right hepatectomy, since the left lateral sector may not
encompass enough future volume. On average, up to
a 15% increase in the total volume of the future liver
remnant can be expected.
PVE can theoretically reduce the risk of
postoperative hepatic dysfunction by inducing
preoperative compensatory hypertrophy of the
non-embolised lobe.
3
As previously identified by our group, a FLR
<30% in patients undergoing liver resection for hilar
cholangiocarcinoma was associated with increased risk
for hepatic insufficiency and death.
63
Moreover, in a
series of 287 consecutive perihilar cholangiocarcinoma
patients who underwent resection, postoperative
mortality at 90days was independently associated with
a FLR <30%.
64
Therefore, the authors recommend
PVE in patients at risk of a FLR of <30%. To date,
numerous studies have reported the safety and efficacy
of PVE in increasing the remnant liver volume before
extended hepatectomy.
74–76
General operative principles
Cholangiocarcinoma remains an aggressive malignancy, and complete tumour extirpation remains
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229
Chapter 13
Percent survival (%)
01
Time (months)
the definitive management and only chance in
achieving long-term survival. Unfortunately,
unresectable or systemic spread of disease is
common at initial presentation. In the setting of
hilar cholangiocarcinoma, only 50–75% of patients
meet resection criteria at diagnosis.
77
At the authors’
institution, 23% of all patients presenting with hilar
cholangiocarcinoma had advanced or unresectable
58
disease.
Additionally, in a review of 53 peripheral
intrahepatic cholangiocarcinomas treated at MSKCC
over an 8-year period, the median tumour diameter
was 7.1 cm at presentation.78 Twenty patients were
found to be unresectable at exploration (overall
resectability rate was 62%). Operative findings
precluding resection were intrahepatic metastases
(35%), peritoneal metastases (30%), coeliac
lymph node metastases (25%) and portal vein
involvement (10%).
78
Additionally, in a more recent
review, a total of 270 patients with intrahepatic
cholangiocarcinoma were seen over a 16-year
period. Of these, 54% had unresectable disease at
presentation and ultimately only 34% of the entire
cohort underwent a potentially curative resection
(70% of those explored with curative intent).
In general, irresectability is defined by bilateral
spread to secondary biliary radicals, bilateral portal
vein involvement, bilateral hepatic arterial
involvement or unilateral hepatic artery involvement
with contralateral ductal spread.70 Moreover, even
when deemed resectable by modern imaging,
30–40% of patients will be deemed unresectable at
the time of exploration. Therefore, diagnostic
laparoscopy has become a prudent step at the time
of operation.
79
laparoscopy spared 27% of patients at MSKCC
undergoing a laparotomy due to findings of
peritoneal and intrahepatic metastases.
78
Margin-negative resection
Whether intrahepatic, hilar or extrahepatic in
origin, the achievement of pathologically negative
margins (R0 resection) is the most predictive factor of
oncologic outcome. This concept has been shown in
previous studies, which found survival for patients
with incomplete (R1 or R2) resections to be
equivalent to those with unresectable tumours
(Fig.13.5).
The extent of resection should be dictated by what
is necessary to achieve a negative margin and this may
require an extended resection. For instance, Bismuth
IIIb lesions typically require a left hepatectomy,
while Bismuth I, II, IIIa lesions usually require an
extended right hepatectomy. Simple excisions of the
extrahepatic biliary tree should be avoided, as this
approach is associated with a high probability of R1/
R2 resections and inferior overall survival.
time, the increased utilisation of hepatic resection
has been responsible for the increased percentage
of R0 resections and the observed improvement
100
75
58
82
Over
R0, 43 months (n = 82)
R1, 24 months (n = 24)
Loc adv, 16 months (n = 29)
Diagnostic laparoscopy
Despite improvements in preoperative imaging,
a considerable number of patients are still
found to have unresectable disease at the time of
exploration. In a recent report from MSKCC,
this number approached 50% of patients with
cholangiocarcinoma explored with curative intent.
24
In an effort to minimise the number of non-curative
laparotomies performed, staging laparoscopy should
therefore be utilised. Two recent studies specifically
analysing patients with biliary cancer have shown
that laparoscopy can identify a large proportion of
patients with unresectable disease primarily in the
form of radiographically occult metastases, the yield
of which is greatest in locally advanced tumours.
80,81
Weber etal. evaluated 56 patients with potentially
resectable hilar cholangiocarcinoma; 33 were
ultimately determined to have unresectable disease,
of which 14 (42%) were identified at laparoscopy
and spared an unnecessary laparotomy.
81
With
respect to intrahepatic cholangiocarcinoma, staging
230
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50
25
0
20040608
Figure13.5 • Survival curves after resection of hilar
cholangiocarcinoma. R0 indicates complete resection
with histologically negative resection margins (median
survival 43months). R1 indicates histologically involved
resection margins (median survival 24months; P <0.001,
R0 vs R1). Loc Adv indicates patients explored, but found
to have unresectable tumours owing to local invasion (no
metastatic disease) (median survival 16months; P <0.19,
R1 vs Loc Adv).
Reproduced with permission from Blumgart LH, editor.
Surgery of the liver, biliary tract, and pancreas. 4th ed.
Elsevier Saunders; 2006.
00
Malignant lesions of the biliary tract
in postoperative survival. This point is emphasised
by a reported series of 269 patients accumulated
over a 20-year period demonstrating a progressive
increase in the proportion of patients subjected to
partial hepatectomy, with a corresponding increase
in the incidence of negative histological margins
and in turn, survival.
83
Moreover, a more recent
study from MSKCC reported results of resection
in 106 consecutive patients and showed a median
survival of 43months in patients who had an R0
resection compared to 24 months in those with
involved resection margins.
24
On multivariate
analysis, R0 resection, concomitant hepatectomy,
well-differentiated histology and papillary tumour
phenotype were all independent predictors of longterm survival.
Intraoperative frozen section should be obtained
and, if positive, extended resections should be
undertaken to obtain pathologically negative
margins. This technique is dictated by the location
of the tumour. For extrahepatic cholangiocarcinoma
frozen section should be obtained on the proximal
and distal bile duct margins and, if positive,
hepatectomy or pancreaticoduodenectomy should
ensue. For perihilar cholangiocarcinoma, distal
and proximal margins should be assessed and, if
positive, extended hepatectomy and/or pancreaticoduodenectomy should ensue. In an MSKCC
analysis of extrahepatic cholangiocarcinoma,
82% of proximal lesions required a combined
hepatectomy whereas 92% of distal lesions
required a pancreatico-duodenectomy.
84
That being
said, there remains doubt as to the true efficacy of
intraoperative frozen section. In an analysis of 90
patients found to have a negative intraoperative
frozen section of the proximal bile duct, 9% were
confirmed positive at final pathology. Therefore,
frozen section analysis of the proximal bile duct
margin was misleading in a substantial subset
of patients. Additionally, in those patients who
were determined to have negative duct margins
intraoperatively, only 60% had margins adequately
wide enough to be associated with an improvement
in disease-specific survival.
If the portal vein is involved with tumour, portal
vein resection should not be considered a
contraindication to resection. Although series have
reported potentially higher postoperative morbidity
and mortality rates, hepatic resection combined with
portal vein resection has been demonstrated to be
associated with superior survival.
85
In an assessment of 95 patients resected for hilar
cholangiocarcinoma, 42 required resection of the
portal vein. Patients who underwent portal vein
resection had perioperative mortality and morbidity
similar to those who did not. Median survival was
38months (95% CI 29–51months), with a 5-year
survival rate of 43%. Similar to the studies reported
above, negative margins were achieved in 84% of
cases and were associated with improved survival
(P <0.01). More impressive, the 5-year survival rate
in patients with an R0 resection was 50%, and on
multivariate analysis the only predictor of survival
was negative margin status.
86
In contrast, the role of arterial resection and
reconstruction is more controversial since the
majority of studies have shown arterial resection and
reconstruction to be associated with significantly
increased morbidity and mortality without longterm survival benefit.
87
Portal lymphadenectomy
In addition to resection margin status (i.e. an R0
resection), metastatic disease to regional lymph nodes
is a critical determinant of outcome. An international
study group for intrahepatic cholangiocarcinoma
has recently advocated routine portal lymph node
dissection at the time of resection, as approximately
30% of patients who underwent evaluation were
found to have lymph node involvement.
Although the survival benefits of node
dissection are unproven and unlikely, the diagnostic
information gained regarding node positivity is
important and may inform decisions about adjuvant
therapy.
Fong etal. found that lymph node status was the
only independent predictor of long-term survival
after complete resection, with positive nodes
conferring a 6.7 times greater likelihood of recurrence
and death.
89
Similarly, Allen etal. reported lymph
node positivity to be an independent predictor of
5-year disease-specific survival (node-negative 42%
vs node-positive 22%) in both proximal and distal
resected cholangiocarcinoma.
84
Lastly, the authors’
group also assessed the prognostic significance of
the highest peripancreatic lymph node. In a series
of 85 patients who underwent curative resection,
30% had a positive peripancreatic lymph node.
This highest peripancreatic lymph node positivity
correlated to statistically lower recurrence-free (24
vs 10 months) and disease-specific survival (62
vs 21 months). Further, on multivariate analysis,
positivity within the highest peripancreatic lymph
node was an independent predictor of recurrencefree survival (HR 3.73, 95% CI 1.86–7.45;
P <0.01) and disease-specific survival (HR 3.98,
95% CI 1.89–8.38; P <0.01).
90
The extent of lymphadenectomy that should be
performed remains an area of controversy. Some
surgeons advocate an extended nodal dissection as
88
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231