This document discusses the surgical management of cholangiocarcinoma, a cancer of the bile ducts. It notes that cholangiocarcinoma most commonly arises from the biliary confluence and can involve the intrahepatic or extrahepatic bile ducts. Complete resection remains the only potentially curative treatment but is often not possible due to advanced disease at presentation. For resectable hilar (biliary confluence) tumors, resection requires a major hepatectomy, while distal tumors typically require pancreaticoduodenectomy. Even with complete resection, recurrence rates are high and adjuvant therapy has not been shown to reduce recurrence. The document outlines approaches for diagnosis, staging, and determining resectability based on tumor

1. Surgical Management of Cholangiocarcinoma
William R. Jarnagin, M.D.,1,2
and Margo Shoup, M.D.2,3
ABSTRACT
Biliary tract cancer affects approximately 7500 Americans each year. Tumors
arising from the gallbladder are the most common; those of bile duct origin, or
cholangiocarcinoma, are less frequently encountered, constituting approximately 2% of
all reported cancers. Although cholangiocarcinoma can arise anywhere within the biliary
tree, tumors involving the biliary confluence (i.e., hilar cholangiocarcinoma) represent the
majority, accounting for 40 to 60% of all cases. Twenty to 30% of cholangiocarcinomas
originate in the lower bile duct, and approximately 10% arise within the intrahepatic biliary
tree and will present as an intrahepatic mass. Complete resection remains the most effective
and only potentially curative therapy for cholangiocarcinoma. For all patients with
intrahepatic cholangiocarcinoma and nearly all patients with hilar tumors, complete
resection requires a major partial hepatectomy. Distal cholangiocarcinomas, on the other
hand, are treated like all periampullary malignancies and typically require pancreaticoduo-
denectomy. Most patients with cholangiocarcinoma present with advanced disease that is
not amenable to surgical treatment, and even with a complete resection, recurrence rates are
high. Adjuvant therapy (chemotherapy and radiation therapy) has not been shown clearly
to reduce recurrence risk.
KEYWORDS: Cholangiocarcinoma, resection, surgery
Objectives: On completion of this article, the reader will be able to (1) discuss issues pertinent to pre-operative assessment and surgical
management of patients with intrahepatic and extrahepatic cholangiocarcinoma, and (2) summarize the results of resection and the role
of adjuvant therapy.
Accreditation: Tufts University School of Medicine (TUSM) is accredited by the Accreditation Council for Continuing Medical Education
to provide continuing medical education for physicians. TUSM takes responsibility for the content, quality, and scientific integrity of this
CME activity.
Credit: TUSM designates this educational activity for a maximum of 1 Category 1 credit toward the AMA Physicians Recognition Award.
Each physician should claim only those credits that he/she actually spent in the educational activity.
Biliary tract cancer affects approximately 7500
Americans each year. The most common tumors are
those that arise from the gallbladder. Cholangiocarcino-
mas, tumors of bile duct origin, are less frequently
encountered and constitute approximately 2% of all
reported cancers.1,2
Although cholangiocarcinoma can
arise anywhere within the biliary tree, tumors involving
the biliary confluence (i.e., hilar cholangiocarcinoma) are
in the majority, accounting for 40 to 60% of all cases.3–10
Of all cholangiocarcinomas, 20 to 30% originate in the
Cholangiocarcinoma: Pathogenesis, Diagnosis, and Management; Editor in Chief, Paul D. Berk, M.D.; Guest Editor, Greg Gores, M.D. Seminars
in Liver Disease, volume 24, number 2, 2004. Address for correspondence and reprint requests: William R. Jarnagin, M.D., Department of Surgery,
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. E-mail: jarnagiw@mskcc.org. 1
Assistant Professor, 2
Department
of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; 3
Department of Surgery, Loyola Medical School, Maywood, Illinois.
Copyright # 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0272-
8087,p;2004,24,02,189,199,ftx,en;sld00275x.
189

2. lower bile duct, and approximately 10% arise within the
intrahepatic biliary tree and will present as an intrahe-
patic mass.11–15
ETIOLOGY
The etiology and risk factors for cholangiocarcinoma are
discussed in detail in the first two articles in this issue.12,13
Several conditions associated with an increased incidence
often have an impact on therapy and are worthy of
mention here. Primary sclerosing cholangitis (PSC) is
perhaps the most common of these in the United States.
PSC is an autoimmune disease characterized by inflam-
mation of the periductal tissues, ultimately resulting in
multifocal strictures of the intrahepatic and extrahepatic
bile ducts.14,15
As many as 40% of patients with PSC have
been found to have cholangiocarcinoma at autopsy.14
Patients with PSC are more likely to have unresectable
multifocal disease than are patients with sporadic cho-
langiocarcinoma. In addition, patients with PSC often
have significant underlying hepatic parenchymal dysfunc-
tion that precludes a major hepatic resection.
Congenital biliary cystic disease (choledochal
cysts, Caroli disease) is also associated with an increased
risk of cholangiocarcinoma.16
Although uncommon
when it is excised early, the incidence of cancer is as
high as 20% in patients who are not treated until after
the age of 20 years or in those previously treated by cyst
drainage.16
Patients with congenital biliary cystic disease
often have an anomalous pancreatobiliary duct union,
and this must be considered when planning resection.
Hepatolithiasis, also known as recurrent pyogenic cho-
langiohepatitis, is prevalent in Japan and in parts of
Southeast Asia and leads to chronic, recurrent episodes
of cholangitis and stricture formation.10,17
Although
sepsis is the major threat to life in these patients,
approximately 10% will develop cholangiocarcinoma.
Biliary parasites (Clonorchis sinensis and Opisthorchis
viverrini) are also prevalent in parts of Asia and are
similarly associated with an increased risk of cholangio-
carcinoma. In Thailand, where approximately 7 million
people are infested with Opisthorchis, the annual in-
cidence of cholangiocarcinoma is among the world’s
highest at 87 per 100,000.18
As with PSC, biliary
parasitic disease is often associated with multifocal sites
of malignancy.
EXTRAHEPATIC CHOLANGIOCARCINOMA
Extrahepatic cholangiocarcinoma, involving the proxi-
mal or distal bile duct, remains a difficult clinical
problem. Most patients with unresectable disease die
within 6 months to 1 year of diagnosis, usually from liver
failure or infectious complications secondary to biliary
obstruction.2,3,19,20
In the past, the prognosis for lesions
arising from the biliary confluence has been considered
to be worse compared with that for distal lesions.
However, patients with hilar tumors often experience a
long delay before referral for resection and less often
have resectable disease. In fact, location alone does not
correlate with survival when the tumor can be completely
resected.5
In the extrahepatic ducts, three distinct macro-
scopic subtypes of cholangiocarcinoma are well-
described: sclerosing, nodular, and papillary.21
Sclerosing
tumors account for most cases and are more common at
the hilus than they are in the distal bile duct. Sclerosing
tumors are very firm and cause an annular thickening of
the bile duct, often with diffuse infiltration and fibrosis
of the periductal tissues. Nodular tumors are character-
ized by a firm, irregular nodule of tumor that projects
into the lumen of the duct. Features of both types are
often seen, hence the frequently used descriptor nodular-
sclerosing. The papillary variant accounts for approxi-
mately 10% of all cholangiocarcinomas and, although
occasionally seen at the hilus, is more common in the
distal bile duct.21
These tumors are soft and friable and
may be associated with little transmural invasion. A
polypoid mass that expands rather than contracts the
duct is a characteristic feature. Although papillary tu-
mors may grow to significant size and appear formidable
on radiographic studies, they often arise from a well-
defined stalk. Frequently, the bulk of the tumor is mobile
within the bile duct (Fig. 1). Recognition of this variant
is important because it is more often resectable and may
have a more favorable prognosis than the other types,
although this has not been proved definitively.
Hilar Cholangiocarcinoma
DIAGNOSIS AND EVALUATION
The first sign of hilar cholangiocarcinoma is jaundice,
but the initial clinical presentation of hilar tumors is
often nonspecific. Many patients will have one or more
nonspecific complaints, such as abdominal pain, anor-
exia, and weight. Although most patients eventually
become jaundiced, those with ipsilateral or segmental
involvement may have abnormal liver function tests and
even pruritus without jaundice. Such findings should
prompt a thorough evaluation. Patients with papillary
cholangiocarcinoma may have tumor fragments in the
distal bile duct, resulting in intermittent jaundice. Cho-
langitis is rarely a presenting feature in patients with
cholangiocarcinoma in the absence of prior biliary in-
tubation but is more common in patients with obstruc-
tion secondary to stone disease.
Imaging studies play a critical role in evaluating
patients with biliary obstruction, and because resection is
the only effective treatment, such studies should be
directed at fully assessing the extent of disease. In
patients with hilar cholangiocarcinoma, evaluation
190 SEMINARS IN LIVER DISEASE/VOLUME 24, NUMBER 2 2004

3. must address four critical components of resectability:
level and extent of tumor within the biliary tree, vascular
invasion, hepatic lobar atrophy, and distant metastatic
disease. Ultrasound is often the first diagnostic study and
will identify the level of obstruction at a minimum
(Fig. 2). However, in experienced hands, duplex ultra-
sonography can provide important information regard-
ing tumor extent within the biliary tree as well as possible
vascular involvement. Cholangiography is an important
investigation for evaluating biliary tumor extent and,
previously, required invasive biliary procedures. Mag-
netic resonance cholangiopancreatography (MRCP) is
currently the authors’ preferred investigation because it
can provide more information than direct cholangiogra-
phy alone can and without the risk associated with biliary
intubation. MRCP will identify the tumor and the level
of biliary obstruction and may reveal obstructed, isolated
ducts not appreciated at endoscopic or percutaneous
study. MRCP also provides information regarding the
hilar vascular structures, lobar atrophy, and nodal or
distant metastases.22–25
Lobar atrophy is an often-overlooked finding in
patients with hilar cholangiocarcinoma. However, its
importance in determining resectability cannot be over-
emphasized, because it often influences therapy. Long-
standing biliary obstruction may cause moderate atro-
phy, whereas concomitant portal venous compromise
induces rapid and severe atrophy of the involved seg-
ments. On cross-sectional imaging, atrophy is character-
ized by a small, often hypoperfused lobe with crowding
Figure 1 (A) Transhepatic cholangiogram showing a
large papillary adenocarcinoma of the proximal biliary
tree (top black arrow) causing bilateral biliary dilata-
tion. Loose tumor fragments are seen in the distal
bile duct (lower black arrow). The transhepatic biliary
catheter is indicated by the white arrow. Note that
the duct in the area of the tumor is expanded rather
than contracted, as is the case with nodular scleros-
ing tumors. (B) Gross photograph of a resected
papillary tumor on cross-section. The bile duct has
been sectioned longitudinally to show the exophytic
tumor growing into the duct lumen. (C) Low-power
view of a hematoxylin and eosin–stained papillary bile
duct cancer showing little invasion into the bile duct
wall.
Figure 2 Ultrasound showing a hilar cholangiocarcinoma
(arrow) with portal vein involvement. The left hepatic duct is
clearly involved (BD). LPV, left portal vein; RPV, right portal vein.
SURGICAL MANAGEMENT/JARNAGIN, SHOUP 191

4. of the dilated intrahepatic ducts (Fig. 3). Thus, the
finding of lobar atrophy implies portal venous involve-
ment and mandates hepatic resection, if the tumor is
resectable.
Most patients with hilar strictures and jaundice
have cholangiocarcinoma. However, alternative diag-
noses can be expected in to 10 to 15% of patients,26
the most common of which are gallbladder carcinoma,
Mirizzi syndrome, and idiopathic benign focal stenosis
(malignant masquerade). Although benign strictures do
occur in the proximal biliary tree, they are uncommon,
and hilar cholangiocarcinoma must remain the leading
diagnosis until definitively disproved. In most cases, this
cannot be done without exploration. Furthermore, it
must be emphasized that the alternative conditions
that one may encounter are best assessed and treated
at surgery, even if benign. Relying on the results of
percutaneous needle biopsy or biliary brush cytology
is dangerous, because the results are often misleading,
and one may miss the opportunity to resect an early
cancer.
The role of preoperative biliary drainage in jaun-
diced patients remains controversial. In reality, most
patients undergo biliary drainage prior to referral for
resection, despite the lack of data showing a benefit.
Clearly, the presence of cholangitis mandates biliary
decompression, but there is no proof that routine biliary
drainage in all patients facilitates resection or reduces
postsurgical morbidity.27,28
On the contrary, the avail-
able data would suggest that biliary stents are associated
with greater postoperative infection complications.38
However, previous studies investigating this issue have
been criticized for several design flaws, and whether
major hepatic resection in the face of biliary obstruction
is associated with a greater risk of liver failure or other
complications remains an open question.30
STAGING
Currently, there is no clinical staging system available
that stratifies patients preoperatively into subgroups
based on potential for resection. The modified Bis-
muth-Corlette classification stratifies patients based
only on the extent of biliary involvement by tumor,31
and the system from the American Joint Committee on
Cancer Staging (AJCCS) is based largely on pathologi-
cal criteria and has little applicability for preoperative
staging. Neither is useful for predicting resectability and
survival. Recently, the authors have proposed a preo-
perative staging system, using data from preoperative
imaging studies, based on biliary ductal involvement,
vascular involvement, and lobar atrophy3,32
(see Table 1).
This clinical T staging system accounts fully for local
tumor extent and correlates closely with resectability and
Figure 3 (A) Cross-sectional MRCP of a patient with hilar cholangiocarcinoma. The tumor involves both the right and the left hepatic
ducts. The left portal vein is occluded, resulting in severe atrophy of the left lobe of the liver, which is shrunken and has dilated and
crowded intrahepatic ducts. Note that the bile ducts in this study appear as white. (B) Intraoperative view showing a severely atrophic
left lobe of liver, which is clearly demarcated from the right liver. The ligamentum teres is being pulled downward and to the left.
Table 1 Proposed Clinical T Stage Criteria for Hilar Cholangiocarcinoma
Clinical Stage Criteria
T1 Tumor involving biliary confluence unilateral extension to 2
biliary radicles
T2 Tumor involving biliary confluence unilateral extension to 2
biliary radicles and ipsilateral portal vein involvement
ipsilateral hepatic lobar atrophy
T3 Tumor involving biliary confluence þ bilateral extension to 2
biliary radicles, unilateral extension to 2
biliary
radicles with contralateral portal vein involvement, unilateral extension to 2
biliary radicles with contralateral
hepatic lobar atrophy, or main portal vein involvement
(Reprinted from Jarnagin et al32
by permission of the publisher)
192 SEMINARS IN LIVER DISEASE/VOLUME 24, NUMBER 2 2004

5. survival. In an analysis of 225 patients with hilar cho-
langiocarcinoma, resectability was nearly 60% in T1
tumors, 31% in T2 tumors, and 0% in T3 tumors.
Survival also decreased with increasing clinical T stage
(Table 2).32
On the other hand, there was no correlation
with survival and stage based on the AJCCS classifica-
tion. In addition, and perhaps more importantly, the
likelihood of distant metastatic disease increased with
more locally advanced lesions (i.e., higher clinical T
stage; see later).
RESECTION
Long-term survival with hilar cholangiocarcinoma de-
pends critically on a complete resection with histologi-
cally negative resection margins. Proper patient selection
requires high-quality, complementary imaging studies
and careful consideration of all of the available data. The
authors’ criteria of unresectable disease are outlined in
Table 3. Distant metastatic disease, advanced cirrhosis,
bilateral tumor extension to second-order intrahepatic
biliary radicles, and encasement or occlusion of the main
portal vein clearly preclude resection. In general, how-
ever, the individual determinants of resectability must be
considered within the context of all findings. Thus,
ipsilateral involvement of the portal vein and bile ducts
may be amenable to resection, whereas contralateral
involvement is usually not. Likewise, ipsilateral lobar
atrophy does not preclude resection, whereas atrophy of
the contralateral lobe does.
Although imaging studies will identify many
patients with unresectable disease, a significant propor-
tion are found to have unresectable disease only at the
time of laparotomy. In the experience at Memorial
Sloan-Kettering Cancer Center (MSKCC), nearly one
third of patients had unresectable tumors at presenta-
tion. However, of the remaining patients with poten-
tially resectable lesions, only 50% underwent resection.
As a result, the authors have increasingly used staging
laparoscopy in an effort to reduce the incidence of
unnecessary open explorations. In a recent analysis of
56 patients with potentially resectable tumors based on
radiological findings, laparoscopy identified unresectable
tumors in 14 (25%).33
The yield was significantly higher
for patients with clinical T2/T3 tumors (12 of 33, 36%)
compared with those with clinical T1 tumors (2 of 23,
9%), which is almost certainly related to the higher
incidence of metastatic disease in the former group.
Laparoscopy detected most patients with peritoneal
or liver metastases but failed to detect all locally un-
resectable tumors. Despite this limitation, however,
laparoscopic staging appears to have a role in these
patients.
Table 2 Stratified by T Stage*
T Stage N
Explored with
Curative Intent Resected
( )
Margins
Hepatic
Resection
Portal Vein
Resection
Metastatic
Disease
Median
Survival (mo)
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
*Six patients had incomplete data and could not be accurately staged. The percentages indicate the proportion of patients within each stage
grouping or of the total number of patients. Metastatic disease refers to metastases to N2 level lymph nodes or to distant sites. Median survival
was calculated for all patients, including those who died perioperatively. (Reprinted from Jarnagin et al32
by permission of the publisher)
Table 3 Criteria of Unresectability
Patient Factors
Medically unfit or otherwise unable to tolerate a major operation
Hepatic cirrhosis
Local Tumor-Related Factors
Tumor 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 tumor extension to secondary biliary radicles
Unilateral tumor extension to secondary biliary radicles with contralateral portal vein branch encasement or occlusion
Metastatic Disease
Histologically proven metastases to N2 lymph nodes*
Lung, liver, or peritoneal metastases
*Metastatic disease to peripancreatic, periduodenal, celiac, superior mesenteric, or posterior pancreaticoduodenal lymph nodes were
considered to represent disease not amenable to a potentially curative resection. By contrast, metastatic disease to cystic duct, pericholedochal,
hilar or portal lymph nodes (i.e., within the hepatoduodenal ligament) did not necessarily constitute unresectability. (Reprinted from Jarnagin
et al32
by permission of the publisher).
SURGICAL MANAGEMENT/JARNAGIN, SHOUP 193

6. In patients with potentially resectable tumors,
there is no doubt that the primary goal of surgery should
be a complete resection with histologically negative
resection margins (i.e., a R0 resection), which at a
minimum requires resection of the extrahepatic biliary
apparatus and subhilar lymphadenectomy. However,
there are now substantial data to suggest that en bloc
partial hepatectomy is also required in most cases. The
results of recent studies show a parallel between the
number of patients undergoing partial hepatectomy and
those having negative resection margins3,32
which is a
potent predictor of outcome (Table 4).32,34–41
In addi-
tion, tumors involving the left hepatic duct almost
always involve the main caudate duct and usually require
a complete caudate resection as well.42
Following resection, 5-year survival rates range
from approximately 20 to 40% (Table 4) and are signi-
ficantly greater in patients who undergo a R0 resection,
typically with a concomitant partial hepatectomy. In the
series from MSKCC, there were no 5-year survivors
(actual or actuarial) among the patients who underwent
bile duct resection alone. Furthermore, survival in pa-
tients with histologically involved resection margins
(R1) was little better than survival in those with un-
resectable, locally advanced tumors was (Fig. 4).
Although 5-year survival after a R0 resection was ap-
proximately 37% in this series, it is notable that cancer
recurrence after 5 years was not uncommon.
Extensive resections for hilar cholangiocarcinoma
have been associated with significant morbidity, and
mortality rates, even at high-volume centers, are on the
order of 5 to 10%. Infective complications are particu-
larly common and often play a central role in post-
operative mortality.32
Several groups have explored the
possible role of preoperative portal vein embolization;
the rationale for this is to induce hypertrophy of the
future liver remnant prior to surgery, thereby potentially
reducing the risk of postoperative hepatic failure.43–45
Although this technique may be of some value, the lack
of compelling controlled data makes it difficult to
advocate its routine use.
Metastatic disease to regional lymph nodes is not
uncommon in patients with hilar cholangiocarcinoma.
In a recent review of 110 patients, Kitagawa et al46
found
that 47% had no involved nodes, 35% had regional
lymph node metastases, and 17% had regional and
para-aortic node metastases. There was a significant
survival difference based on nodal status. Node-negative
patients had 3- and 5-year survival rates of 55% and 30%,
respectively, compared with 32 and 14.7%, respectively,
for those with regional nodal metastases and 12.3% in
both cases for those with para-aortic node metastases.46
In the series from MSKCC, microscopic involvement of
lymph nodes in the hepatoduodenal ligament did not
significantly reduce survival, although this observation
may be the result of inadequate sample size. It remains to
be proved that extended lymph node dissection offers a
survival advantage in hilar cholangiocarcinoma. In the
authors’ view, metastatic disease to lymph nodes beyond
the hepatoduodenal ligament (celiac, para-aortic, and so
on) is a contraindication to resection.
ADJUVANT THERAPY
Several studies have investigated the use of postoperative
adjuvant radiation therapy, with mixed results.34,47–49
None of these studies was randomized, and most consist
of a small, heterogeneous group of patients treated with a
variety of regimens. At the present time, there are no
data to support the routine use of adjuvant or neoadju-
vant radiation therapy, except in the context of a con-
trolled trial. Likewise, there is currently no role for
adjuvant chemotherapy.
PALLIATION
Complete resection is associated with a 30 to 40% 5-year
survival. However, most patients are not candidates
for resection, and the primary goal of therapy is palliat-
ing the effects of biliary obstruction. Palliative biliary
Table 4 Association Between Concomitant Partial Hepatectomy and R0 Resections (Negative Margins) in Patients
with Hilar Cholangiocarcinoma*
Author
Complete Gross
Resection (n)
Concomitant Partial
Hepatectomy (%)
R0 Resections
(%)
5-Year Survival
(%)y
Cameron et al34
39 20 15 8
Gerhards et al35
112 29 14 —
Su et al36
49 57 24 15
Hadjis et al37
27 60 56 22
Jarnagin et al32
80 78 78 27
Klempnauer et al38
147 79 79 28
Neuhaus et al39
95 85 61 22
Kosuge et al40
65 88 88 33
Nimura et al41
55 98 83 40
*Data from published series.
y
Reflects survival for all resected patients.
194 SEMINARS IN LIVER DISEASE/VOLUME 24, NUMBER 2 2004

7. drainage is clearly necessary in patients with intractable
pruritus or recurrent cholangitis. In addition, most
nonoperative therapies require normalization of the
serum bilirubin, and drainage will be necessary in these
patients as well. Percutaneous biliary drainage and sub-
sequent placement of a self-expandable metallic endo-
prosthesis (Wallstent) is the preferred approach and can
be successfully performed in most patients with hilar
obstruction. Endoscopically placed stents are usually
ineffective for proximal biliary obstruction. It should
be emphasized that biliary stenting is not appropriate
in all cases. For example, it is important to recognize that
placement of biliary drainage catheters in an atrophic
lobe will not relieve jaundice and should therefore be
avoided, unless performed to control infection.
Patients found to have unresectable, locally ad-
vanced tumors at operation may be candidates for in-
trahepatic biliary-enteric bypass. Not infrequently,
unresectability is discovered only after an extensive dis-
section, including transection of the distal bile duct, and
re-establishment of biliary-enteric continuity becomes
necessary. In such cases, the segment III duct is often
accessible, although the right anterior or posterior sec-
toral hepatic ducts can also be used.50
In a review of 55
consecutive bypass procedures in patients with malignant
hilar obstruction, the authors found segment III bypass
yielded the best results, with a 1-year bypass patency rate
of 80%.50
An advantage of this approach is that the
anastomosis is away from the tumor and less susceptible
to recurrent obstruction due to disease progression.
Palliative radiotherapy has been used in patients
with unresectable, localized disease. External beam radia-
tion therapy, sometimes combined with intraluminal
iridium-192, can be performed safely and with minimal
serious complications and mortality.51
Although there
may be some improvement in survival with this approach,
a clear benefit has never been demonstrated in a prospec-
tive fashion. Some authors have reported no benefit and
question its routine use, given the increased incidence of
complications and greater time spent in hospital.52
Distal Bile Duct Adenocarcinoma
Adenocarcinoma of the distal bile duct represents ap-
proximately 10% of all periampullary tumors. Progres-
sive jaundice is seen 75 to 90% of the time with other
symptoms, including abdominal pain, weight loss, fever,
and pruritus, occurring in one third or fewer cases.4,53
It
may be difficult preoperatively to distinguish distal bile
duct cancer from ductal adenocarcinoma of the pancrea-
tic head. Imaging studies showing a distal bile duct stric-
ture with proximal dilatation and a normal appearing
Figure 4 Survival following resection for hilar cholangiocarcinoma. R0 resections (margin negative)—solid black line, median
survival ¼ 43 months (n ¼ 67). R1 resections (margin positive)—broken black line, median survival ¼ 24 months (n ¼ 21). Locally
advanced tumors, unresectable at exploration—solid gray line, median survival ¼ 14 months (n ¼ 33). (MSKCC, unpublished data, 1991–
2001.)
SURGICAL MANAGEMENT/JARNAGIN, SHOUP 195

8. pancreatic duct would suggest a diagnosis of bile duct
cancer. In reality, it is unnecessary to pursue diagnostic
studies to distinguish between these lesions because the
operative management is the same. Once choledocho-
lithiasis has been excluded as a cause of distal bile duct
obstruction, the possibility of a malignancy must be
considered. As with proximal lesions, distal biliary stric-
tures will be benign in a small proportion of patients, but
proving this definitively without resection is often not
possible. Endoscopic ultrasonography may be helpful by
identifying a mass in the distal duct as the cause of the
obstruction. In general, patients with jaundice and distal
common bile duct obstruction rarely need histological
confirmation of the diagnosis prior to resection, provided
they understand that a benign diagnosis may be made on
the final specimen.
Good quality cross-sectional imaging is impor-
tant to assess resectability. Many patients are referred
after endoscopic retrograde cholangiopancreatography
and stent placement. In those who have not been
subjected to direct cholangiography, MRCP can provide
all of the necessary information regarding level of ob-
struction and biliary tumor extent and may, in addition,
identify vascular involvement or distant metastatic dis-
ease, or both.
Complete resection is the only effective therapy
for cancers of the lower bile duct.4,5,8,53
Five-year survi-
val rates of up to 40% have been reported after complete
resection, but survival beyond 1 year is uncommon in
patients subjected to palliative bypass or biliary intuba-
tion. Complete resection generally requires a pancreati-
coduodenectomy. As with hilar cholangiocarcinoma,
there is no proven benefit of adjuvant therapy following
complete resection.
INTRAHEPATIC CHOLANGIOCARCINOMA
Intrahepatic cholangiocarcinoma (IHC), also referred to
as peripheral cholangiocarcinoma or cholangiolar carci-
noma, arises from intrahepatic biliary radicles. A recent
report has documented a dramatic increase in the in-
cidence and mortality related to IHC in the United
States,54
and similar observations have been made in
Europe and Japan.55
Despite this, IHC remains uncom-
mon in western countries but may account for up to 30%
of primary liver malignancies in some parts of Asia,56
where biliary parasitic infestation is common.
Unlike the much more common hepatocellular
carcinoma, IHC is infrequently associated with chronic
underlying liver disease, although recent reports have
suggested an association between IHC and chronic
hepatitis C infection.55,57
Because IHC is a rare disease,
progress in elucidating the pathogenesis and clinical
behavior of these tumors has been slow. However, the
increasing number of reports in recent years has in-
creased awareness of IHC and provided some insight
into its biology. Much effort has been directed at under-
standing the differences in clinical behavior among the
different macroscopic subtypes, for which three major
variants are recognized: (1) the mass-forming type,
which forms a well-circumscribed hepatic mass; (2) the
periductal infiltrating type spreads along the intrahepatic
bile ducts; and (3) the intraductal type. A mixed mass-
forming plus periductal infiltrating subtype has also been
described.58
The mass-forming type is the most common
but is associated with poor survival after resection,
especially compared with the intraductal variant.59
Diagnosis
Early symptoms with IHC are uncommon, and, as a
result, patients often present with large hepatic tumors,
with pain being the most common symptom. Other
nonspecific symptoms include malaise and weight loss.
Pruritus and jaundice may occur in up to one third of
patients and result from compression or invasion of the
biliary confluence.
Not infrequently, patients are investigated for
nonspecific abdominal complaints and are found to
have one or more hepatic lesions. In some patients, these
tumors reach sizable proportions before they come to
attention (Fig. 5). Imaging studies generally show a
relatively avascular soft tissue mass in the liver without
biliary or gall bladder dilatation. On magnetic resonance
imaging, they are hypodense or isodense on T1-weighted
images and hyperdense on T2-weighted images. Com-
puted tomography (CT) scans usually show a hypodense
mass, often with central necrosis, that is indistinguish-
able from a metastatic lesion. IHC are typically more
hypovascular than hepatocellular carcinomas are. Rou-
tine blood work often indicates normal hepatic function,
no evidence of chronic hepatitis, and a normal a-feto-
protein level. In many cases, patients are subjected to a
percutaneous biopsy that reveals adenocarcinoma. This
typically leads to a preliminary diagnosis of metastatic
liver disease, and the diagnosis of IHC is often not
considered until an extensive investigation fails to iden-
tify a primary tumor. In many cases, an experienced
pathologist can support the diagnosis of IHC based on
immunohistochemical staining of the biopsy specimen;
however, it is not possible to make a definitive diagnosis
on a biopsy specimen alone. Patients suspected of having
IHC should therefore be thoroughly investigated to
exclude an extrahepatic primary lesion (CT scan of chest
and abdomen).
Staging
Currently there is no useful clinical staging system
for peripheral cholangiocarcinomas. The AJCCS tumor,
nodes, and metastases classification for primary liver
cancer is applied to both hepatocellular carcinoma and
peripheral cholangiocarcinoma and is of little practical
196 SEMINARS IN LIVER DISEASE/VOLUME 24, NUMBER 2 2004

9. value. Recently, Okabayashi et al60
proposed a new
staging system for mass-forming intrahepatic cholangio-
carcinoma. Based on 60 patients undergoing hepatic
resection for mass-forming IHC, the authors devised a
system to predict the differences in survival after resec-
tion: Stage I disease was defined as a solitary tumor
without vascular involvement, Stage II was defined as a
solitary tumor with vascular encasement, Stage IIIA was
defined as multiple tumors, Stage IIIB was defined as
any tumor with regional nodal metastasis, and Stage IV
was defined as any tumor with distant metastases. The
3-year survival rates based on this staging system were
74, 48, 18, and 7% for Stages I, II, IIIA, and IIIB,
respectively.60
Resection
As with extrahepatic cholangiocarcinoma, complete re-
section of IHC is the most effective treatment and the
only therapy associated with prolonged disease-free
survival. IHC are often large at presentation, and most
patients require major hepatic resections for complete
tumor clearance (right or left hepatectomy or extended
hepatectomy).61
Unfortunately, many patients present
with disease beyond the limits of surgical therapy. Over-
all resectability of IHC is difficult to estimate, however,
because most studies lack an accurate denominator. In a
recent review of 53 patients with potentially resectable
tumors at MSKCC, 33 patients underwent resection and
20 had radiographically occult unresectable disease. Like
many reports, this study did not include the total number
of patients with IHC seen during the study period.
In the MSKCC study, median and 5-year survival
were 37.4 months and 31%, respectively, in patients
submitted to resection compared with 11.6 months
and 0% for those with unresectable disease, and this is
consistent with other series (Table 5).62–67
Predictors of
poor survival in this report were vascular encasement,
multiple tumors, and histologically positive resection
margins, all of which have been identified in other
reports. Sixty-one percent of patients in the resection
group recurred at a median of 12.4 months, and the liver
was overwhelmingly the most common site of failure.
The presence of vascular involvement, multiple tumors,
and large tumor size were predictive of disease recur-
rence. It is of interest that the presence of microscopic
disease in regional lymph nodes did not correlate with
recurrence or survival, but there were only five such
patients in this study.61
In a separate report, Isa et al68
found that none of the 5-year survivors after resection of
IHC had involved nodes nor infiltrating periductal type
lesions, suggesting that both lymph node status and
tumor type correlate with outcome. Whether lymph
node dissection improves survival has not been clearly
demonstrated.
CONCLUSION
Cholangiocarcinoma remains a devastating disease.
Most patients have unresectable tumors at the time of
diagnosis and have a dismal prognosis. Nonoperative
therapy has a limited impact. Complete resection is the
only treatment that offers any hope of long-term survival
Table 5 Survival After Resection of Intrahepatic
Cholangiocarcinoma—Results of Selected Series
Author
Patients
(n)
Median
Survival (mo)
5-Year
Survival (%)
Pichlmayr et al62
32 13 –
Jan et al63
41 12 27
Casavilla et al64
34 – 31
Madariaga et al65
34 19 35
Valverde et al66
30 28 22
Inoue et al67
52 18 36
Figure 5 Chest radiograph (A) and CT scan (B and C) of a patient with a large peripheral cholangiocarcinoma. The final resected specimen
was 20 cm in greatest diameter. Note the marked elevation of the right hemidiaphragm on the chest radiograph as a result of the tumor.
SURGICAL MANAGEMENT/JARNAGIN, SHOUP 197

10. but is possible in a few patients. Furthermore, even after
resection, disease recurrence is common. Adjuvant ther-
apy has not been shown to have a role in this disease.
Clearly, more active systemic agents are necessary for
most patients with unresectable tumors and those who
recur after resection.
ABBREVIATIONS
AJCCS American Joint Committee on Cancer Sta-
ging
IHC intrahepatic cholangiocarcinoma
MRCP magnetic resonance cholangiopancreatogra-
phy
MSKCC Memorial Sloan-Kettering Cancer Center
PSC primary sclerosing cholangitis
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