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In most centers, direct cholangiography is used to evaluate the extent of biliary involvement and

provide palliation for jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) has little role

to play in high biliary obstruction because opacification of the proximal biliary tree is difficult. ERCP,

however, can be effectively used to image more distal lesions. At the time cholangiography is

performed, some authors advocate the routine preoperative placement of biliary drainage catheters to

aid in intraoperative identification of the bile ducts.77,78 Others have found a higher incidence of

infectious complications and mortality, and a longer hospital stay, after preoperative placement of

biliary drainage catheters.79–81 The difficulty in making the decision regarding preoperative stenting is

that many patients are severely symptomatic because of jaundice and pruritus and require palliation,

thus if the operation is delayed, many patients require palliation.

Figure 63-5. Computed tomography scan in a patient with hilar cholangiocarcinoma, demonstrating dilated intrahepatic ducts in

the right lobe but inability to directly visualize tumor.

Figure 63-6. Coronal (A) and axial (B) magnetic resonance imaging in a patient with hilar cholangiocarcinoma. Dilated

intrahepatic ducts are present with a soft tissue density consistent with tumor (arrows).

Figure 63-7. Coronal (A) magnetic resonance imaging and magnetic resonance cholangiopancreatography (B) in a patient with

hilar cholangiocarcinoma, demonstrating dilated intrahepatic ducts narrowing at the area of obstruction.

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In many cases, it is difficult to obtain pathologic confirmation of cholangiocarcinoma except in very

advanced cases, even with the use of biliary brushings and cytology obtained at the time of direct

cholangiography. In most cases, patients are offered surgical therapy based on clinical suspicion and

radiographic appearance. In patients with ICC, cross-sectional imaging with CT scan is usually sufficient.

Tumors may be masslike or may have cystic areas.

Surgery

Untreated, most patients with bile duct cancers die within a year of diagnosis.81,82 Surgical excision is

the treatment of choice, with no other potentially curative therapy available. The immediate causes of

death are most commonly hepatic failure or cholangitis related to tumor growth and inadequate

drainage of the biliary tree.83 Therefore, the goals of surgery are complete removal of tumor with R0

margins while leaving a sufficient liver remnant, and establishing adequate biliary drainage. Patients

with ICC require additional consideration. Those patients with multifocal and especially bilobar

intrahepatic tumors, even if technically resectable with negative margins and adequate remnant liver,

should not be considered for resection. These patients have very poor prognosis indicating that bilobar

hepatic spread represents hematogenous metastasis.84 What remains controversial is whether

peritumoral satellite lesions also represent metastatic disease. Because this is unknown and surgery is

the only potentially curative therapy for these patients, satellite lesions are not currently considered a

contraindication to resection.

Hilar cholangiocarcinoma is often unresectable due to local factors. These include invasion of the

main portal vein or both the right and left portal veins and hepatic arteries and tumor extension into

second-order biliary radicals of both right and left hepatic lobes. By contrast, tumors extending into

second- or third-order biliary radicles on one side of the liver without vascular involvement can be

resected for cure. It has become clear over the last three decades that curative treatment for patients

with tumors of the hilum or those involving the upper half of the bile duct depends on aggressive

excision that often requires a major liver resection. Until as recently as one decade ago, treatment of

hilar cholangiocarcinomas was associated with mortality as high as 30%.85–89 Recently, major

improvements in the safety of these operations have been demonstrated, and resection of hilar tumors

now results in mortality of less than 10%, even when liver resections are required.85,86,88,90

Role of Staging Laparoscopy

Because of the potential morbidity of a laparotomy that has no therapeutic benefit, staging laparoscopy

has been advocated to save patients from unnecessary laparotomy. In patients with hilar

cholangiocarcinoma, up to 25% will benefit from staging laparoscopy because of detection of occult

extrahepatic disease.33,34 Laparoscopy is a very sensitive means to detect peritoneal metastases or

additional intrahepatic disease through the use of laparoscopic ultrasound but is less sensitive in

detecting nodal metastases or locally invasive tumors.

Partial Hepatectomy With or Without Bile Duct Resection

The extent of hepatectomy required for resection of cholangiocarcinoma is dependent on the tumor

location in relation to the portal inflow and venous outflow of the liver. Intraoperative ultrasound is a

useful adjunct for assessment of tumor extent and for small satellite lesions that may not be apparent on

cross-sectional imaging.

Small ICCs may be removed by segmentectomy or sectorectomy, but these tumors are often large and

require extended right or left hepatectomy. For hilar and proximal hepatic duct lesions, complete

resection usually requires combined biliary and hepatic resection with or without major vascular

reconstruction. Additionally, caudate resection is often required because of direct extension into caudate

biliary radicles or parenchyma.74,89,91 Resection of the extrahepatic bile duct with Roux-en-Y

hepaticojejunostomy to the remnant duct is required in these cases. Intraoperative assessment of the

bile duct resection margin should be performed if additional duct can potentially be taken. If not,

assessment on permanent sectioning is sufficient.

Lymphadenectomy

Regional lymphadenectomy is essential for accurate staging of cholangiocarcinoma, and may be

important for locoregional disease control, but has historically been underperformed for intrahepatic

and hilar tumors.73,92 Recent data have shown that lymph node metastases are present in 30% to 40% of

patients.73,92–94 Regional lymph nodes include those along the porta hepatis, the hepatoduodenal

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ligament, the hepatic artery for essentially all patients. In addition, for those with primary tumors of

the right hemiliver, retropancreatic nodes should be removed. For those with primary tumors of the left

hemiliver, perigastric lesser curve nodes (levels 1, 3, and 5) should be removed.95 As is true for

gallbladder cancer, there is currently no consensus on the minimum number of lymph nodes needed for

accurate staging of cholangiocarcinoma.

Pancreaticoduodenectomy

For cholangiocarcinoma of the lower half of the extrahepatic bile duct, pancreaticoduodenectomy is

requiring for complete tumor extirpation. The proximal bile duct margin should be assessed by frozen

section to ensure tumor clearance. Regional lymphadenectomy is inherent in this procedure.

Liver Transplantation for Hilar CC and the Mayo Protocol

Orthotopic liver transplantation (OLT) was thought to hold promise for patients with hilar CC, because

of the ability to achieve adequate margins by complete hepatectomy. Unfortunately, when used as a

single treatment modality, results have been poor. Three- and 5-year survival rates have been reported

at 25% to 30%.96–98 Because of this poor outcome, the Mayo Clinic developed a protocol combining

neoadjuvant therapy with liver transplant, based on a strategy initially developed by the University of

Nebraska. This protocol uses high-dose neoadjuvant 5-fluorouracil and brachytherapy followed by liver

transplantation.99,100 Inclusion criteria include (i) locally advanced unresectable disease with either

positive intraluminal brush cytology, positive intraluminal biopsy, or CA19-9 ≥100 in the setting of a

radiographic malignant stricture; (ii) primary sclerosing cholangitis with resectable disease; and (iii)

absence of medical contraindications for OLT. Since 2003, biliary aneuploidy as demonstrated by digital

image analysis (DIA)(77) and fluorescent in situ hybridization have been considered equivalent to

cytology.101 Exclusion criteria include (i) extrahepatic disease including regional lymph node

involvement; (ii) uncontrolled infection; (iii) prior attempt at resection; (iv) prior treatment with

radiation or chemotherapy; and (v) previous malignancy within 5 years. In this protocol, patients

receive external beam radiotherapy to a target dose of 4,500 cGy with concomitant fluorouracil (5-FU).

Following this, transcatheter iridium-192 brachytherapy with a target dose of 2,000 to 3,000 cGy is

administered. Thereafter, patients receive oral capecitabine as tolerated until transplantation. It is

important that, prior to transplantation, patients undergo a staging laparotomy, at which time biopsy of

perihilar lymph nodes as well as any lymph nodes or nodules suspicious for tumor is performed. Only

patients with negative staging operations remain eligible for transplantation.99

RESULTS

Table 63-7 Results after Resection for Hilar Cholangiocarcinoma

Patients eligible for OLT under this protocol have locally advanced tumors but no pathologic nodal

disease. The prolonged course of neoadjuvant therapy, staging laparotomy, and time on the OLT

waiting list provides an opportunity to exclude patients demonstrating disease progression. This highly

rigorous selection bias in favor of patients with biologically favorable disease is reflected in the early

outcomes published from the Mayo group. In a recent review of 71 patients enrolled in this transplant

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protocol, only 38 underwent transplantation (38%). These patients were compared to 26 patients (of 54

explored, 48%) who underwent successful resection. When compared to those undergoing resection

(some with node-positive disease), patients undergoing transplantation were younger (p < 0.001) and

more likely to have inflammatory bowel disease (p < 0.03) and PSC (p < 0.001). It is important that

only 58% of patients had histologically proven cancer. In these highly disparate groups, 5-year survival

was 82% after transplantation (38 patients) compared to 21% after resection of 26 patients (p =

0.022).97 There were also fewer recurrences in the transplant patients (13% vs. 27%), and recurrences

became apparent later after transplantation than after resection (mean 40 months vs. 21 months). Direct

comparisons are difficult with this study given the differences between groups.

At present, OLT cannot be considered a standard form of therapy for hilar cholangiocarcinoma for

patients with resectable disease, but it does offer a potential option for patients with underlying PSC or

those with unresectable tumors who fit the rigorous inclusion and exclusion criteria of the protocol.

Prognosis After Resection

Results of major studies on resection of hilar cholangiocarcinoma are summarized in Table 63-7. In

patients amenable to curative resection, the median survival is 35 months with a 5-year survival rate of

10% to 30%.79,87,88,96,100,110 Surgical resection provides both improved survival and improved quality of

life. The greatest risk factors for recurrence include the presence of positive margins, and node-positive

tumors.111

In patients with ICC, expected 3-year survival rates as high as 60% have been reported, with 5-year

survival rates of 30% to 45%.35,111,112 Patients with unresectable disease have a median survival of 12

months.35,113 Thus, completely resected ICC appears to have an improved prognosis over proximal

(hilar) cholangiocarcinoma. Patients with cholangiocarcinomas arising in the distal bile duct have both

an increased resectability rate and improved prognosis over those with hilar cholangiocarcinomas.90

Patients with resectable distal bile duct cancer have a 5-year survival rate of 30% to 50%, with a

decreased survival if nodes are involved with tumor.114,115

Unresectable Cholangiocarcinoma

6 For patients with unresectable hilar cholangiocarcinomas, significant improvement in quality of life

can be achieved with surgical bypass. Palliative bypass can be performed in several ways. A partial

excision of the left lateral segment and biliary-enteric anastomosis to the left hepatic duct (Longmire

procedure) was used commonly in the past, but more recently surgical techniques have become less

complicated and do not require hepatic parenchymal transection. One technique involves biliary

decompression through the left duct, approached through the round ligament, a segment III bypass (Fig.

63-8). Opening the bridge of tissue just beneath the ligamentum teres allows access to the duct. In this

position, a long anastomosis can be performed from the segment III duct to a jejunal limb because of

the horizontal course of the duct in this location. Although less commonly used, the right hepatic duct

can be approached at the base of the gallbladder fossa. This is technically more difficult and results in a

higher rate of late bypass failure.116

Nonoperative palliative biliary decompression can be accomplished with percutaneous or endoscopic

stenting, depending on the level of obstruction. Proximal lesions are usually approached percutaneously

with placement of expandable stents or drainage catheters (Fig. 63-9). Internal stents result in fewer

electrolyte abnormalities and improvement in patient comfort, although morbidity and mortality occurs

in up to 30% of patients and stent occlusion is common.117–119 There is a significant risk of cholangitis

with external and internal drainage, occurring in more than 90% of patients with metallic expandable

internal stents in one series.118 Bleeding and bile leaks are also frequent complications. More recent

techniques (e.g., photodynamic therapy) have been used to palliate patients with biliary obstruction and

may hold some promise for the future.120

Because patients with unresectable disease have a short median survival, those whose disease is

clearly unresectable on preoperative imaging should undergo percutaneous internal or external

drainage. In patients who undergo exploratory surgery and whose disease is found to be unresectable,

surgical bypass offers fewer episodes of cholangitis, with an improved quality of life. In some series,

surgical bypass for patients with unresectable disease is the only biliary drainage procedure ever

required by the patient.

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Figure 63-8. Surgical approach to segment III duct. A: The bridge of tissue present at the base of the liver is divided. B: The

ligamentum teres is held superiorly to expose the tissue overlying the segment III duct. C: The segment III duct is exposed. D: The

duct is opened in preparation for anastomosis with a Roux-en-Y jejunal limb. (Courtesy of Dr. L. H. Blumgart.)

In patients with unresectable distal cholangiocarcinomas, palliation can be achieved with surgical

bypass, percutaneous biliary drains, or ERCP-placed stents. The simplest and most effective way to

relieve jaundice is usually with an ERCP stent. Although surgical bypass offers improved patency and

fewer episodes of cholangitis, the morbidity of the procedure is not warranted in patients with these

aggressive tumors.

Adjuvant Therapy

To date, no chemotherapeutic regimen has consistently shown activity against cholangiocarcinoma.

Many of the issues that pertain to chemotherapy trials in gallbladder cancer are directly relevant to the

interpretation of trials for cholangiocarcinomas. Studies performed to date have typically been small,

single-institution trials, including patients with both gallbladder and bile duct cancers.121

Although 5-fluorouracil (5-FU)–based chemotherapy is often offered to patients with unresectable

disease, the likelihood of response is less than 10%. Capecitabine as a single agent may have some

modest activity in cholangiocarcinomas.122 When capecitabine was used in combination with

gemcitabine in a recent prospective study, overall survival was 14 months.65 Gemcitabine and cisplatin

combination therapy has also been tested in phase II studies of patients with advanced biliary tract

carcinoma.123,124 Results of these studies demonstrated response rates of 27% to 34.5%, and overall

survival of 9.7 to 11 months. The use of mitomycin C and doxorubicin (Adriamycin), in combination

with 5-FU, has resulted in combined response rates of less than 30%, with higher toxicity than 5-FU

alone.125

With the exception of extrahepatic disease, there is no clear role for adjuvant chemotherapy in the

treatment of cholangiocarcinoma. The previously mentioned phase II trial from 2015 showed a

promising 2 year survival for patients with extra hepatic cholangiocarinoma treated with adjuvant

capecitabine/gemcitabine and concurrent capecitabine and radiation therapy.62 Aside from this study,

however, previous data suggested no difference in overall survival (36% vs. 42%, p = 0.6) or loco

regional recurrence (38% vs. 37%, p = 0.13) in patients who underwent R0 resection alone versus

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those with high loco regional recurrence risk who received adjuvant chemoradiation therapy.126 Similar

to the recommendations for gallbladder cancer, patients with extra hepatic cholangiocarcinoma who

undergo R0 or R1 resection should be considered for adjuvant capecitabine/gemcitabine and concurrent

capecitabine and radiation therapy.

In cases of unresectable cholangiocarcinoma, the use of external beam radiation therapy has been

explored.91,127–130 To date, no study has clearly demonstrated efficacy for this modality. Anecdotal

reports of long-term survivors after external beam radiotherapy show that some individuals may benefit

from such treatment, but this must be weighed against the potential complications (e.g., duodenal or

bile duct stenosis and duodenitis). The most encouraging results involve use of intraoperative or

interstitial radiation.127,128,130,131 Our current practice is to use combined interstitial radiation and

external beam radiation in unresectable cases after palliative bypass. In patients whose disease is

resected and have node- or margin-positive disease, systemic therapy with gemcitabine or 5-FU, or 5-

FU–based chemoradiation, or enrollment in a clinical trial should be strongly encouraged.

Figure 63-9. A: Percutaneous transhepatic cholangiogram in a patient with hilar cholangiocarcinoma, demonstrating biliary

obstruction at the confluence. The patient has previously had placement of internal/external stents for biliary drainage. B: Film

demonstrates appearance of wall stents after deployment into the left and right biliary ducts. C: After stenting, the cholangiogram

demonstrates adequate biliary drainage, with contrast filling the duodenum.

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