Surg Clin N Am 88 (2008) 1409–1428

Proximal Biliary Malignancy

Mohamed Akoad, MD, FACSa,
Roger Jenkins, MD, FACSb,*
a
Division of Hepatobiliary and Liver Transplantation, The Lahey Clinic Medical Center,
41 Mall Road, 4 West, Burlington, MA 01803, USA
b
Division of Surgery, The Lahey Clinic Medical Center, Tufts University School of Medicine,
41 Mall Road, 4 West, Burlington, MA 01803, USA

Malignant strictures involving the proximal bile ducts present diagnostic

and therapeutic challenges to all specialties involved in its management.
They can result from metastatic spread of nonbiliary tumors (eg, pancreas,
gallbladder, stomach, colon and rectum, lymphoma) to the hepatic hilum or
from primary biliary cancer (cholangiocarcinoma). Cholangiocarcinoma
comprises less than 10% of primary hepatic malignancies and can arise
from the intrahepatic or extrahepatic bile ducts [1]. Although these tumors
can occur at any level of the biliary tree, 67% occur at the bifurcation of the
bile duct (hilar cholangiocarcinoma) [2], where they are often referred to as
Klatskin tumors [3]. These tumors often invade major branches of the portal
vein and the hepatic artery, making resection difficult.
Surgical resection with negative margins carries the only hope for long-
term survival. Recently, innovative aggressive techniques combining hepatic
resection and hilar vascular resection have increased the number of patients in
whom resection with negative margins is achieved [4–7]. A protocol combin-
ing neoadjuvant therapy with liver transplantation is currently undergoing
evaluation at several transplant centers. Patients with unresectable hilar tu-
mors are candidates for palliative biliary drainage to prevent the development
of cholangitis and hepatic failure. Without treatment, death from liver failure
generally occurs within 3 to 6 months from initial clinical presentation.

Incidence
Extrahepatic bile duct cancers are relatively rare tumors with an inci-
dence of 0.01% to 0.2% in large autopsy series [8]. The reported incidence

* Corresponding author.
E-mail address: roger.l.jenkins@lahey.org (R. Jenkins).

0039-6109/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.suc.2008.07.012 surgical.theclinics.com
1410 AKOAD & JENKINS

in the United States is about 1 to 2 cases per 100,000 patients [9]. The disease
is more frequently diagnosed in the fifth and sixth decade of life, and there is
a slight male predominance [10].

Etiology
Although the etiology of cholangiocarcinoma is obscure, it has been sug-
gested that chronic inflammation of the biliary system or exposure to toxic
agents concentrated in bile might result in DNA damage in the biliary epi-
thelial cells leading to malignant transformation. In a recent report, 94% of
resected specimens from patients with cholangiocarcinoma stained positive
for the tumor suppressor p53 gene, and 100% stained positive for prolifer-
ating cell nuclear antigen (PCNA) [11]. Moreover, K-ras proto-oncogene
mutations were found in 75% of specimens from patients with cholangiocar-
cinoma [12].
Certain disorders have been associated with an increased incidence of
cholangiocarcinoma. Primary sclerosing cholangitis (PSC), an autoimmune
disease characterized by multifocal strictures of the intrahepatic and extra-
hepatic bile ducts, is known to be associated with an increased incidence of
cholangiocarcinoma. Unlike most cases of sporadic cholangiocarcinoma of
the extrahepatic biliary tree, patients who have PSC are at an increased risk
of multifocal disease that may not be amenable to resection. The incidence
of cholangiocarcinoma in patients with PSC is unknown, but incidental
cholangiocarcinoma was found in 4% to 8.6% of liver explants of patients
who underwent liver transplantation for PSC [13,14]. Choledochal cysts and
Caroli’s disease are congenital disorders that carry an increased risk of chol-
angiocarcinoma. The risk of malignant degeneration increases to 15% to
20% for patients not treated until adulthood. The reason for the increased
risk of cholangiocarcinoma in patients with congenital biliary cysts is not
clear but is thought to be related to the abnormal entry of the pancreatic
duct into the bile duct, resulting in reflux of pancreatic juice into the biliary
tree. The resulting chronic inflammation may predispose to the development
of cholangiocarcinoma. Bile stasis and chronic inflammation within the cyst
may also be a predisposing factor [15–17].
Cholangiocarcinoma is more prevalent in Southeast Asia than anywhere
else in the world. This prevalence is thought to be related to parasitic infec-
tion with the liver flukes Clonorchis sinensis and Opisthorchis viverrini. These
liver flukes gain entry to the host through the duodenum and reside in the
bile ducts. The resulting chronic biliary obstruction leading to stricture for-
mation and chronic inflammation is thought to predispose to cancer [18].
Oriental cholangiohepatitis, which is prevalent in Japan and parts of South-
east Asia, is characterized by chronic portal bacteremia leading to sepsis and
pigment stone formation. Chronic cholangitis and stricture formation have
been thought to be predisposing factors for cholangiocarcinoma, which is
present in 10% of patients with oriental cholangiohepatitis [19].
 PROXIMAL BILIARY MALIGNANCY 1411

Associations with some chemical carcinogens or drugs have been reported,

such as oral contraceptives [20], methyldopa [21], isoniazid [22], and
asbestos [23].

Pathology
Three distinct macroscopic subtypes of cholangiocarcinoma have been
described: sclerosing, nodular, and papillary [24]. The sclerosing variety is
the most common and causes annular thickening of the bile duct with infil-
tration and fibrosis of adjacent tissues. These tumors are locally invasive and
tend to invade periductal neural tissues as well as major vascular structures
of the hilum. The nodular variety is characterized by irregular intraluminal
nodules. When both features are present, the tumor is described as nodular-
sclerosing. The papillary variant, which accounts for 10% of cases, is a soft
and often friable tumor. These tumors are less likely to cause periductal
fibrosis or invade adjacent structures, and they have a more favorable out-
come than other variants.
Microscopically, more than 95% of tumors are adenocarcinomas ranging
from well to poorly differentiated varieties [9,25]. Cholangiocarcinomas are
mucin-secreting adenocarcinomas, and intracellular mucin can often be
demonstrated. Immunohistochemical staining for epithelial membrane anti-
gen and tissue polypeptide antigen may be useful in confirming the diagnosis
of cholangiocarcinoma. Submucosal tumor spread is an important feature
of cholangiocarcinoma. This subepithelial spread beyond the obvious tumor
emphasizes the importance of wider resections and confirmation of negative
margins by frozen section during the resection operation. Other histologic
types such as squamous, leiomyosarcoma, rhabdomyosarcoma, and cysta-
denocarcinoma are rare.
Hilar cholangiocarcinoma is often slow growing; however, rapid progres-
sion has been seen in some patients. Spread by direct invasion to periductal
hilar tissues with invasion of portal vein branches as well as hepatic arterial
branches is a common feature of hilar cholangiocarcinoma. Direct invasion
of adjacent liver tissue is also common. Regional lymph node involvement is
present in 30% to 50% of cases, whereas blood-borne metastasis to the
lungs, kidneys, bones, or brain is rare [24].

Clinical presentation
The clinical presentation of hilar cholangiocarcinoma varies with the site
of origin but most commonly begins with painless jaundice. Intense gener-
alized pruritus may develop months before the onset of jaundice when the
site of tumor origin is in the main left or right hepatic duct. It has long
been recognized that unilateral obstruction of the bile ducts results in atro-
phy of the corresponding lobe and compensatory hypertrophy of the contra-
lateral lobe (Fig. 1) [26]. The ability of the contralateral lobe of the liver to
1412 AKOAD & JENKINS

Fig. 1. (A) CT scan of a patient with hilar cholangiocarcinoma and long-standing right ductal
obstruction resulting in atrophy of the right lobe and compensatory hypertrophy of the left
lobe. (B) Findings at exploration showing sharply demarcated atrophic right lobe.

hypertrophy in the presence of complete biliary obstruction often delays the

development of symptoms. Anorexia and fatigue are nonspecific symptoms
that develop in the majority of patients; constant pain is an ominous sign
that often (but not always) portends metastatic spread to surrounding tis-
sues. Fever is unusual in the absence of instrumentation of an intact biliary
tree despite a 30% incidence of bacterobilia [27]. Most patients have few
symptoms and come to attention when they become jaundiced or when
they are found to have abnormal liver function tests. Apart from jaundice
and skin excoriation in patients with pruritus, physical examination is gen-
erally unremarkable.
Total serum bilirubin is elevated in most patients with hilar cholangiocar-
cinoma at presentation and is usually greater than 10 mg/dL. Alanine ami-
notransferase and aspartate aminotransferase are usually mildly elevated.
Serum alkaline phosphatase and gammaglutamyl transferase are elevated
in 90% of patients with cholangiocarcinoma even in the absence of
hyperbilirubinemia [28]. In contrast to hepatocellular carcinoma, alpha-
fetoprotein is rarely elevated in patients with cholangiocarcinoma. The level
of carcinoembryonic antigen (CEA) is elevated in 40% to 60% of patients
and carbohydrate antigen 19-9 in 80% [29].

Radiologic evaluation
Once a patient is diagnosed with obstructive jaundice based on clinical and
laboratory data, the initial radiologic modalities are abdominal ultrasonog-
raphy and abdominal CT scan. Ultrasonography is useful in differentiating
hilar obstruction from other causes of obstructive jaundice, such as carci-
noma of the head of the pancreas, ampullary tumors, gallbladder carcinoma,
and choledocholithiasis. In patients with hilar cholangiocarcinoma, ultra-
sound often demonstrates a dilated intrahepatic biliary tree and a collapsed
 PROXIMAL BILIARY MALIGNANCY 1413

common bile duct and gallbladder. The gallbladder may be distended if the
lesion extends distally to occlude the cystic duct orifice. In specialized centers,
ultrasonography can identify with reasonable accuracy the presence of a mass
and can delineate the extent of the tumor. It can also assess hepatic artery and
portal vein patency through Doppler flow imaging [30].
Corporal imaging by CT or MRI scanning is essential in further evalua-
tion of the patient and ideally should be performed before endoscopic retro-
grade cholangiopancreatography (ERCP) or percutaneous transhepatic
cholangiography (PTC). The modality used is dependant on the quality of
imaging available at a particular institution. In many centers, magnetic
resonant cholangiopancreatography (MRCP) (Fig. 2) has become an in-
valuable tool in preoperative assessment of patients with hilar cholangiocar-
cinoma and has almost replaced endoscopic and percutaneous
cholangiography [31,32]. MRCP is helpful in staging cholangiocarcinoma
and determining resectability by providing information regarding tumor
size, the extent of bile duct involvement, vascular invasion, extrahepatic
extension, nodal or distant metastases, and the presence of lobar atrophy.
The accuracy of MRCP for the assessment of tumor status, periductal infil-
tration, and lymph node metastases is 90%, 87%, and 66%, respectively
[33]. The triphasic CT scan performed in a high-speed scanner is currently
the authors’ preferred modality for hepatic imaging (Fig. 3). When properly
timed, this study can give accurate imaging of hilar vascular anatomy in
conjunction with changes in subsegmental hepatic anatomy. Such images
can be enhanced to provide three-dimensional mapping of projected surgical
planes by providing accurate information about the relationship between
the tumor and the adjacent vascular structures (Fig. 4) [34].

Fig. 2. MRCP of a patient with malignant hilar stricture (arrow).

1414 AKOAD & JENKINS

Fig. 3. Triphasic CT scan of a patient with hilar cholangiocarcinoma showing dilatation of the
intrahepatic biliary tree. (A) Arterial phase. (B) Portal venous phase.

Fig. 4. (A) Three-dimensional image reveals narrowing of the portal vein. Resection of a 3-cm
segment is required (long thick line). The right hepatic artery is also involved by tumor. The lines
of transection of the proper hepatic artery and right hepatic artery are planned (small arrows).
(B) Three-dimensional image in the cranial projection. Arrowed line indicates the planned line
of resection, just to the left side of the R-point. (From Endo I, Shimada H, Sugita M, et al. Role
of three-dimensional imaging in operative planning for hilar cholangiocarcinoma. Surgery
2007;142(5):672; with permission.)
 PROXIMAL BILIARY MALIGNANCY 1415

Despite the emergence of newer imaging modalities as tools for the eval-
uation of proximal biliary strictures, cholangiography remains an important
diagnostic modality after corporal imaging in many centers. It demonstrates
the location and extent of the tumor and delineates the segmental biliary
anatomy, which is helpful in planning the hepatic resection. Cholangiogra-
phy allows both identification and drainage of obstructed ducts. Both
ERCP (Fig. 5) and PTC (Fig. 6) have been used with success for preopera-
tive tumor assessment as well as biliary drainage. In operable patients, the
authors prefer ERCP with drainage of the uninvolved lobe. ERCP can be
difficult to perform in patients with hilar cholangiocarcinoma and carries
the risk of cholangitis and post procedure pancreatitis; however, in special-
ized large-volume centers, ERCP can be performed with a high success rate
and low morbidity [35,36]. Despite the tightly obstructing nature of proxi-
mal hilar tumors, an experienced endoscopist can often demonstrate the
proximal biliary anatomy and establish biliary drainage of the obstructed
lobe or lobes. Close communication between the endoscopist and surgeon
is vital to adequately delineate the tumor extent and to establish appropriate
drainage of the obstructed segments. If endoscopic drainage is not successful
or if jaundice persists despite adequate drainage, the authors perform unilat-
eral or bilateral PTC to establish drainage to obstructed segments.
The 18F-fluorodeoxyglucose positron emission tomography (PET) scan
is currently being used with increasing frequency to assist with the diagnosis
of hilar cholangiocarcinoma [37]. Currently, the PET scan is not used rou-
tinely to diagnose hilar cholangiocarcinoma but has been used in patients
with PSC, in whom it can be extremely difficult to identify a malignant

Fig. 5. ERCP of a patient with hilar cholangiocarcinoma showing dilatation of the intrahepatic
bile ducts. The arrow points to the stricture.
1416 AKOAD & JENKINS

Fig. 6. (A) PTC in a patient with hilar cholangiocarcinoma and jaundice not relieved by ERCP
stenting of the left hepatic duct. (B) The guidewire is passed through the stricture into the com-
mon bile duct.

stricture in the background of chronic widespread intrahepatic biliary stric-

tures [38]. It is also being used to confirm recurrent cancer after resection. In
a recent study evaluating the use of the PET scan in patients with biliary
cancer, it identified occult metastatic disease and changed management in
24% of patients [39].
If patients are surgical candidates, efforts to establish preoperative tissue
diagnosis by examining bile cytology, brush cytology, or endoscopic ultra-
sound–guided fine-needle aspiration are not essential. The sensitivity of
bile cytology is only 24% and that of brush cytology 59% [40]. A negative
cytology report in the presence of a hilar stricture should never dissuade the
clinician from treating the stricture as a malignancy in the appropriate clin-
ical setting. Endoscopic biliary brushings for cytology are only important
when the patient is not a surgical candidate.

Preoperative biliary drainage

The value of preoperative biliary drainage for malignant obstructive
jaundice remains controversial. Several prospective randomized studies
have found no benefit from preoperative biliary drainage in malignant ob-
structive jaundice from all causes [41–43]. Moreover, a recent meta-analysis
found that preoperative biliary drainage did not reduce operative morbidity
or mortality in patients with malignant obstructive jaundice [44]; however,
most of these studies lacked uniformity and included predominantly patients
with distal bile duct obstruction from pancreatic cancer, ampullary tumors,
or distal cholangiocarcinoma. In these studies, patients with proximal bile
duct malignancy comprised only 12.1%. To date there are no prospective
 PROXIMAL BILIARY MALIGNANCY 1417

randomized studies examining the efficacy of preoperative biliary drainage

in patients with proximal bile duct tumors; however, several retrospective re-
ports support its use [45–47]. Proximal bile duct tumors comprise a different
group because, unlike for distal malignant bile duct obstruction, major he-
patic resection constitutes a major component of the resection operation.
Extended hepatic resection in patients with complete obstructive jaundice
and cholangitis carries a risk of bleeding, sepsis, and severe postoperative
hepatic failure [48,49]. Preoperative drainage of obstructed yet salvageable
hepatic segments allows resolution of the induration and cholestasis of the
involved hepatic parenchyma with more prompt bile excretion in the post-
operative period. Results of Japanese series show that preoperative biliary
drainage increases resectability and tolerance after major hepatectomy
[7,50].
The authors routinely perform preoperative percutaneous or endoscopic
biliary drainage of the obstructed lobes or segments if they are anticipated to
be important salvageable segments of hepatic parenchyma. To reduce the
risk of postoperative hepatic failure, surgery is usually delayed until the total
bilirubin levels fall below 2.5 to 3.0 mg/dL.

Patient selection and assessment of resectability

Preoperative staging and assessment of resectability are accomplished by
radiologic studies with the goal of identifying potential candidates for sur-
gery and planning the extent of resection. The currently widely used Bis-
muth-Corlette classification allows comparative stratification of tumor
spread along the bile ducts but does not address portal vein or hepatic artery
involvement. The classification is useful in operative planning but does not
predict resectability or survival [51]. Many patients with types I and II
spread may achieve better outcomes with wider resections including hepa-
tectomy [4–7,45,46]. A new preoperative staging system developed by Burke
and colleagues [52] stratifies patients according to the degree of biliary
involvement, hepatic lobar atrophy, and ipsilateral or bilateral portal vein
involvement (Table 1). This staging system has been reported to have better
correlation with resectability than the Bismuth classification. Findings of
bilobar peripheral hepatic metastasis or extrahepatic disease preclude resec-
tion, as does bilateral duct involvement up to the secondary biliary radicals.
Unilateral involvement of the portal vein or hepatic artery is treated by
ipsilateral hepatic lobectomy and is not a contraindication to resection.
More advanced tumors with bilateral vascular involvement need careful pre-
operative assessment and planning because they may require more advanced
vascular techniques with portal vein and hepatic arterial reconstruction and
represent relative contraindications.
The overall general medical condition and fitness of the patient for oper-
ation, which usually includes major hepatectomy, should be carefully eval-
uated. Preoperative assessment should include evaluation of the cardiac risk,
1418 AKOAD & JENKINS

Table 1
Proposed T stage criteria for hilar cholangiocarcinoma
Stage Criteria
T1 Tumor confined to confluence and/or right or left hepatic duct without portal vein
involvement or liver atrophy
T2 Tumor confined to confluence and/or right or left hepatic duct with ipsilateral liver
atrophy No portal vein involvement demonstrated
T3 Tumor confined to confluence and/or right or left hepatic duct with ipsilateral portal
venous branch involvement with/without associated ipsilateral lobar liver atrophy. No
main portal vein involvement (occlusion, invasion, or encasement)
T4 Any of the following: (1) tumor involving both right and left hepatic ducts up to the
secondary radicals bilaterally, or (2) main portal vein encasement
From Burke EC, Jarnagin WR, et al. Hilar cholangiocarcinoma: patterns of spread, the
importance of hepatic resection for curative operation, and a presurgical clinical staging system.
Ann Surg 1998;228(3):385–94; with permission.

pulmonary status, and liver and renal function. Nutritional status is gener-
ally assessed and nutritional support initiated as indicated. Coagulopathy
should be corrected with the administration of vitamin K. Cholangitis
should promptly be controlled with the appropriate antibiotics.

Treatment
Resection of hilar malignancies remains one of the most difficult opera-
tions in surgery and is heavily dependent on the experience and expertise
of the operating surgeon. Nevertheless, surgical resection represents the
only successful treatment for cure or significant prolongation of life. The
nature of the surgery is determined by the proximal and distal extent of
the tumor as defined by preoperative imaging and the anatomic characteris-
tics of the neighboring vascular inflow. The surgical goal is resection of all
regional nodal tissue and the common bile duct (and gallbladder) en bloc
with the requisite portion of liver to achieve negative microscopic margins.
The authors perform diagnostic laparoscopy at the initiation of the
surgical procedure to exclude patients with unrecognized metastases from
major laparotomy. A right subcostal incision is used with upward midline
extension to the xiphoid to provide exposure for resection. The peritoneal
cavity is again inspected for evidence of regional or distant metastasis,
and the liver is examined for evidence of metastasis not recognized by pre-
operative radiologic studies. The duodenum is kocherized to begin resection
of the lymphoid tissue lateral and posterior to the common bile duct. We
begin dissecting the lymphatic and neural tissue at the level of the celiac
artery and proceed to skeletonize the common hepatic artery and its
branches. The common bile duct is transected at the superior edge of the
pancreas, and all lymphatic and neural tissue lateral and posterior to the
bile duct is mobilized en block, skeletonizing the proper hepatic artery as
well as the portal vein (Fig. 7). Dissection is carried cephalad including
 PROXIMAL BILIARY MALIGNANCY 1419

Fig. 7. (A, B) Skeletonization of the portal vein and hepatic artery. IVC, inferior vena cava;
LHA, left hepatic artery; LHD, left hepatic duct; MHA, segment IV artery; PV, portal vein;
RHA, right hepatic artery; RPV, right portal vein.

the gallbladder in the specimen. As more proximal mobilization of the bile

duct continues, assessment of involvement of the hepatic artery and portal
vein branches allows the operator to determine the need for vascular resec-
tion and reconstruction. The bile ducts are eventually divided at the second-
ary biliary radicals on the hepatic segments to be retained. This maneuver
usually entails dividing the duct above the juncture of the right anterior
and posterior branches on the right for left side dominant tumors or the seg-
mental branches on the left for right side dominant tumors. The inflow and
outflow vasculature of the hepatic lobe to be removed with the specimen is
then divided, and the parenchyma transaction is performed using a combina-
tion of finger and instrument fracture. The resected liver lobe is removed in
continuity with the specimen.
Extended right or left hepatectomies are sometimes necessary to achieve
negative margins [4–7,45,46,52–54]. Biliary branches from the caudate lobe
can represent an unsuspected repository of residual tumor after bile duct
resection for cancer; therefore, most authorities advocate en bloc resection
of the caudate lobe with bile duct tumors [45,55,56].
Because of the proximity of the tumor to the major vascular structures in
the hilum of the liver, vascular invasion is common. Unilateral involvement
is treated by ipsilateral hepatic lobectomy. More advanced vascular tech-
niques with portal vein and hepatic arterial reconstruction are required to
resect more advanced tumors with bilateral vascular involvement. The au-
thors’ approach to these complex advanced tumors is to completely excise
the tumor and re-establish vascular inflow (portal vein and hepatic artery)
to the remaining hepatic lobe. This task sometimes requires resection of
the portal vein at the bifurcation and anastomosis of the main portal vein
to the right or left portal vein. Similarly, arterial reconstruction might be
required using microvascular techniques (Figs. 8, 9). Many of these more
1420 AKOAD & JENKINS

Fig. 8. (A) Hilar cholangiocarcinoma involving the portal vein bifurcation requiring resection
of the portal vein. (B) Blood flow to the remnant lobe is re-established by anastomosing the
main portal vein to the right portal vein.

advanced techniques have evolved directly as a result of our growing expe-

rience with living donor liver transplantation. Many reports have shown
that this aggressive surgical approach increases the number of patients in
whom complete excision of the tumor with negative margins can be achieved
with acceptable morbidity and mortality [50,57–59].
Reconstruction of the biliary tree with a Roux-en-Y limb of jejunum
completes the procedure. Frequently, with high resection into the secondary
biliary radicals, multiple bile ducts require proper drainage after removal of
the specimen. This drainage can be simplified by converting two or three
neighboring ducts into a single orifice by dividing the septum between
them and suturing the adjacent walls together. The anastomosis is per-
formed using 5-0 polydioxanone sutures by laying the posterior layer first
and completing the anterior layer over a pediatric feeding tube passed
through the proximal end of the roux as a biliary stent. The biliary stents
allow easy access for postoperative radiologic confirmation of biliary

Fig. 9. (A) Bilateral involvement of the hepatic artery and portal vein requiring resection of the
portal vein bifurcation and both right and left hepatic arteries involved with tumor. (B) Flow to
the remnant lobe is established by sewing the main portal vein to the right portal vein and the
proper hepatic artery to the right hepatic artery using microvascular techniques.
 PROXIMAL BILIARY MALIGNANCY 1421

anatomy and are removed 3 to 4 weeks after discharge. Closed suction

drainage is routinely performed.

Adjuvant therapy
Currently, there are no data supporting the routine use of adjuvant or
neoadjuvant therapy in patients with hilar cholangiocarcinoma. Radiother-
apy using external beam radiation delivering doses of up to 60 Gy with du-
odenal protection has been used as an adjunct to surgical resection in
patients with positive surgical margins. In a prospective study, Pitt and col-
leagues [60] found that adjuvant radiotherapy had no effect on overall sur-
vival. Percutaneous and endoscopic endoluminal radiation techniques as
well as radioimmunotherapy with 131I-anti-CEA have also been used in
combination with systemic chemotherapy in patients with cholangiocarci-
noma with little benefit. Nevertheless, some retrospective studies have
shown some survival advantage with adjuvant radiotherapy [61,62]. These
studies were nonrandomized and included a heterogeneous group of
patients. Moreover, many multivariate analyses looking at neoadjuvant
therapy among other factors have identified resection with negative histo-
logic margins as the only factor associated with prolonged survival [4–
6,45]. Similarly, single agent or combination chemotherapy has failed to
show efficacy. Drugs such as 5-fluorouracil (5-FU), methansulfon, cisplatin,
mitomycin C, paclitaxel, and gemcitabine have shown little efficacy, with
response rates ranging from 0% to 9% and median survivals between 2
and 12 months [63]. A prospective randomized trial comparing oral 5-FU
with oral 5-FU plus streptozotocin and oral 5-FU plus methyl-CCNU in
patients with unresectable cholangiocarcinoma demonstrated a response
rate of only 9% [64]. Presently, there are no data to support the routine use
of adjuvant chemoradiation, except in controlled trials. Despite the lack of ev-
idence, adjuvant chemoradiation is used at the many centers around the world.
The authors reserve the use of adjuvant chemoradiation for patients with pos-
itive nodal status or microscopically positive bile duct margins.

Results
Long-term survival can be achieved with acceptable morbidity and
mortality. The perioperative mortality rate ranges from 1.3% to 11%,
and morbidity rates range from 35% to 50% [4–7,45,46,65–67]. The pres-
ence or absence of positive histologic margins in the resected specimen is
an important determinant of disease recurrence and patient survival [4–
6,46,68,69]. The early experience with local hilar resection was associated
with a high incidence of positive margins and poor long-term survival [2].
With growing experience in the management of hilar cholangiocarcinoma,
the number of patients undergoing hepatic resection has increased steadily.
Moreover, the addition of sophisticated vascular reconstructions to the
1422 AKOAD & JENKINS

surgical armamentarium has led to an increase in the number of patients un-

dergoing R0 resection. This aggressive surgical approach has increased the
number of patients undergoing curative resections and has been associated
with improved patient survival. Five-year survival rates as high as 59% have
been reported [70]; however, the 5-year survival rates in most recent reports
range from 20% to 45% [4–7,45,46,65–67,71,72].
Combining hepatic resection with portal vein resection for locally
advanced tumors has increased the resectability rate with acceptable
morbidity and mortality. These complex vascular resections are technically
difficult and may increase the risk of the procedure. Some authorities have
reported worse 5-year survival in patients who undergo portal vein resection
[50], whereas others have reported a similar outcome to those without portal
vein resection [57,73].

The Lahey Clinic experience

The authors’ program started in 1985 at the former New England Dea-
coness Hospital and moved to the Lahey Clinic in 1999. From 1985 to
2007, 124 patients with hilar cholangiocarcinoma underwent resection
with curative intent. As our experience evolved, we adopted a more radical
aggressive surgical approach with the addition of hepatectomy and complex
vascular reconstruction to achieve negative surgical margins. When compar-
ing our earlier experience between 1985 and 1999 (period 1) [74] with that
between 1999 and 2007 (period 2) (Mohamed Akoad, MD, FACS, unpub-
lished data, 2008), local and hepatic resection was performed in 75.9% of
patients in period 2 as compared with 48.6% in period 1. Combined vascular
resection was performed in 17 patients (3 in period 1 and 14 in period 2).
Portal vein resection only was performed in 13 patients, hepatic artery resec-
tion only in 2, and both hepatic artery and portal vein resection in 2. Neg-
ative margins were achieved in 86.8% in period 2 compared with 50% in
period 1(P!.05). The perioperative mortality rate was 6% in period 1
and 5% in period 2. The 1-, 3-, and 5-year survival rates in period 1 were
83.1%, 56.1%, and 13.6%, respectively, as compared with 89.1%, 56%,
and 32.5%, respectively, in period 2 (P ¼ .007). The overall 1-, 3-, and
5-year survival rates in patients with R0 resection were 92.9%, 67.5%,
and 38.3%, respectively, compared with 72%, 3.5%, and 0%, respectively,
for R1 resections. Clearly, the improvement in survival is a result of the ap-
plication of wider resections with the addition of partial hepatectomy and
vascular resections.

Palliation
Extensive surgical resection should only be carried out with the goal of
achieving complete tumor removal and negative histologic margins. In
patients who are not candidates for surgical resection due to bilateral
 PROXIMAL BILIARY MALIGNANCY 1423

extensive biliary involvement, bilateral vascular invasion not amenable to

reconstruction, or extensive regional spread, management options include
adequate biliary drainage and preventing infectious complications.
The relief of jaundice can be achieved by surgical or nonsurgical means.
To date, randomized studies comparing surgical palliation with nonopera-
tive biliary drainage have demonstrated no difference in survival time, com-
plication rates, or the relief of jaundice; therefore, surgical bypass should
only be considered in patients who are found to be unresectable at opera-
tion. Because most of these patients have preoperative biliary drainage, sur-
gical bypass is rarely indicated [75–77]. If surgical bypass is considered, we
prefer to perform hepaticojejunostomy to bile ducts far away from the upper
extent of the tumor to prevent obstruction from rapid tumor growth. Only
one lobe of the liver needs to be bypassed to maintain adequate function.
Traditionally, anastomosis to the segment III bile duct at the base of the
round ligament has been the most common drainage option. Bypass of an
atrophic lobe or a lobe heavily involved with tumor is generally ineffective.
Nonoperative biliary drainage can be accomplished by an endoscopic or
percutaneous approach. In patients with advanced tumor, the endoscopic
approach has a high failure rate. Percutaneous biliary drainage and subse-
quent placement of biliary stents can be performed in most patients with
hilar cholangiocarcinoma. The self-expandable metallic wall stents provide
a more durable option (Fig. 10) [78,79]. Regardless of whether an endo-
scopic or percutaneous approach is used, the presence of an atrophic lobe
is an important factor to be considered before the drainage procedure.
Drainage of an atrophic lobe does not provide relief of jaundice and should
be avoided. Sometimes multiple stents may be required to adequately drain
the obstructed segments and provide palliation. Recurrent jaundice after

Fig. 10. Metal wall stents placed percutaneously in a patient with unresectable hilar
cholangiocarcinoma.
1424 AKOAD & JENKINS

wall stent placement occurs in approximately 18% to 28% of patients

because of tumor growth through the mesh of the wall stent or beyond
the proximal or distal margins of the stent [79,80]. Biliary drainage can be
re-established by adding a longer stent place inside the existing stent. Jaun-
dice that fails to subside after adequately draining all of the segments is
likely due to hepatic dysfunction from prolonged obstruction or vascular
compromise from tumor invasion and is not likely to be corrected with
drainage procedures.

Liver transplantation
Logic would suggest that total hepatectomy and liver transplantation
would be the best treatment option because adequate margins are more eas-
ily obtained; however, the initial experience with liver transplantation for
hilar cholangiocarcinoma has been plagued by early mortality, high recur-
rence rates, and poor survival. The Cincinnati Transplant Tumor Registry
reported a 5-year survival rate of 28% with a 51% tumor recurrence rate
[81]. Most patients who underwent liver transplantation for cholangiocarci-
noma died within 1 to 2 years due to rapid aggressive disease recurrence
[82,83]. More aggressive regional resections, including bile duct resection
and pancreaticodudenectomy to eradicate the entire biliary tree and achieve
a wide margin, followed by liver replacement and upper abdominal exenter-
ation with subsequent cluster transplantation (liver, pancreas, duodenum,
and variable amounts of jejunum) have not demonstrated any added benefit,
with few long-term survivors [84,85]. These results have led many centers to
abandon liver transplantation for cholangiocarcinoma to avoid wasting the
scarce donor organ, and cholangiocarcinoma has become an exclusion cri-
terion for liver transplant.
Recently, a protocol combining radiotherapy, chemosensitization, and
liver transplantation has resulted in a dramatic improvement in outcome,
with 1-, 3-, and 5-year survival rates of 92%, 82%, and 82%, respectively
[86–88]. These results were significantly better than those of resection alone;
however, comparing the results between these two groups was difficult,
because the medical selection criteria were more stringent for the transplant
group, and patients were significantly younger and with higher incidences of
PSC than the resection group. Nevertheless, this approach provides the
most promising and encouraging treatment strategy for hilar cholangiocar-
cinoma and is worth further evaluation.

Summary
Hilar cholangiocarcinoma is a rare malignancy that occurs at the bifurca-
tion of the bile ducts. Complete surgical excision with negative histologic
margins remains the only hope for cure or long-term survival. Because of
its location and proximity to the vascular inflow of the liver, surgical
 PROXIMAL BILIARY MALIGNANCY 1425

resection is technically difficult and may require advanced vascular recon-

structions to achieve complete excision. Despite advances in surgical tech-
niques, the 5-year survival rate in most recent reports ranges from 20% to
45%. The role of neoadjuvant therapy and liver transplantation in the man-
agement of hilar cholangiocarcinoma remains to be defined in light of recent
promising results. Patients with advanced unresectable tumors and patients
who are not candidates for surgical resection because of other comorbidities
are candidates for palliative biliary drainage.

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