Tumor location may be important in determining the extent of resection. If the tumor arises in the

gallbladder infundibulum, the CBD is often involved with tumor, either by direct extension or external

invasion of the hepatoduodenal ligament. In this case, an extended liver resection and removal of a

portion of the CBD should be performed. Reconstruction is then performed by Roux-en-Y

hepaticojejunostomy. Tumor arising in the fundus of the gallbladder, however, can be treated with

limited hepatic resection without excision of the CBD. Complete regional lymphadenectomy should be

performed, skeletonizing the CBD, hepatic artery, and portal vein. Short-term postoperative outcomes

following resection of gallbladder cancer have remained relatively stable over time, with postoperative

morbidity occurring in 30% to 40% of patients, and mortality occurring in <5% (Table 63-4).

Incidentally or Laparoscopically Discovered Gallbladder Cancer

Gallbladder cancer is often discovered during pathologic examination after cholecystectomy for

presumed benign disease. Because of the popularization of laparoscopic cholecystectomy in the past

decade, an increasing number of patients with gallbladder cancer are found incidentally. Patients with

T1b or greater tumors and no signs of distant disease should be offered exploration and further

resection to eradicate all diseases. In a series of 135 patients who underwent reexploration following

laparoscopic cholecystectomy, 61% of all and 36% of those with T1b primary tumors were found to

have residual disease.54 In this study, survival following reresection of residual locoregional disease was

extremely poor and was not different from that of patients with metastatic disease. Improved survival

has been demonstrated following reresection to achieve negative margins, however, especially in

patients with T2 or T3 disease.51,55,56 While laparoscopic port-site recurrence has been reported, it is

associated with peritoneal-based disease. Port-site excision at the time of reexploration is no longer

recommended as recent data have shown that it is not associated with decreased recurrence or improved

survival.57,58

Reresection after recent cholecystectomy is often technically challenging. Postoperative inflammation

in the right upper quadrant often hinders distinction of tumor from normal tissue. Bile spillage at the

time of the initial operation may result in carcinomatosis.59 Determination of ductal or nodal

involvement by tumor is always difficult at the time of reoperation. In addition, postoperative fibrosis

often encases the right hepatic artery, which crosses behind the bile duct in most patients. Because of

this, during a second operation for incidentally discovered gallbladder cancer, an extended right

hepatectomy along with excision of the extrahepatic biliary tree and portal lymphadenectomy is often

necessary. This resection allows adequate exposure for lymphadenectomy and greater confidence of a

negative margin on the bile duct, and also permits biliary reconstruction to only one side of the liver.

The disadvantage is that a large portion of normal liver parenchyma is sacrificed, and consequently,

transient postoperative liver dysfunction is common. Although it may be more difficult to curatively

resect disease in patients with incidentally discovered gallbladder cancer after laparoscopic

cholecystectomy, there is no difference in overall survival between patients with incidentally discovered

gallbladder cancer who are submitted to curative resection and those patients who undergo initial

curative resection.50

When a patient presents with T1a gallbladder cancer discovered after simple cholecystectomy, the

pathology should be reviewed to determine if the entire gallbladder has been removed and if the cystic

duct margin is clear of tumor. If the cystic duct margin is positive, the patient requires bile duct

excision. If all margins are negative, no further therapy is warranted. If the tumor is proved to be T1b

or greater, complete staging should be performed. In the absence of metastatic disease, patients should

be counseled regarding reexcision to attempt complete resection, chemotherapy with or without

radiation, or observation. Patients with a known or suspected early gallbladder carcinoma should be

referred to an experienced center where curative-intent resection can be performed at the initial

operation.

Adjuvant Therapy

Adjuvant therapy for gallbladder cancer remains a controversial and unproved consideration and is

rarely utilized.45 Very few randomized trials have been completed, and the conclusions that can be

drawn from them are limited given the small sample sizes. Given the relative rarity of these

malignancies in the United States, large-scale, randomized trials are feasible only in the context of a

multi-institutional or cooperative group setting.

In 2002, a randomized phase III trial of adjuvant chemotherapy with 5-fluorouracil and mitomycin C

versus surgery alone for patients with pancreaticobiliary malignancies having resection found that in the

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subset of patients with gallbladder cancer (n = 112), the 5-year survival rate was significantly better in

the adjuvant group (26%) versus the control group (14%).60 Similarly, the 5-year disease-free survival

rate was 20.3% versus 11.6%, clearly favoring the adjuvant therapy group. A recent review of the SEER

database also reported an association between adjuvant chemoradiation therapy and improved survival

in patients with locoregionally advanced disease.61 This finding prompted a multi center phase II trial of

adjuvant capecitabine and gemcitabine followed by concurrent capecitabine and radiation therapy for

patients with resected gallbladder cancer or extra hepatic cholagiocarcinoma. The results of this study

were published in 2015 and showed promising findings of 65% two-year survival.62 These studies

suggest that patients with gallbladder cancer with high risk for recurrence (T2 or greater, node-positive,

or margin-positive) should be considered for adjuvant treatment with systemic chemotherapy or

chemoradiation.

Table 63-4 Complications Postoperative Morbidity Following Resection of

Gallbladder Cancer Over Time in the United States56

Prognosis

The 5-year survival rate for all patients with gallbladder cancer is less than 5% in most series, with a

median survival of 6 months. This is primarily because most patients present with unresectable disease.

Of those patients undergoing resection, survival is dependent on depth of penetration and nodal status.

Nearly 100% survival is reported after simple cholecystectomy for T1a disease, whereas patients with

T2 and T3 tumors without nodal disease have a 5-year survival greater than 50%.14,15,40,52 Node

positivity is an ominous finding, with few series reporting 5-year survivors.

Follow-up after Resection for Gallbladder Cancer

The most common sites of recurrence after resection of gallbladder cancer include carcinomatosis,

intrahepatic metastases, or nodal recurrence in the retroperitoneum. For most tumors, local recurrence

is found synchronously with diffuse intra-abdominal spread. Therefore, surgical treatment of recurrence

has little potential for cure. The main goal of surgery after recurrence of resected gallbladder cancer is

to provide palliation of symptoms such as pruritus or cholangitis associated with jaundice, or bowel

obstruction associated with carcinomatosis. When jaundice or cholangitis is the presenting symptom of

possible recurrence, a nonsurgical palliative approach using percutaneous transhepatic cholangiogram

(PTC) and stenting is usually favored unless a benign postsurgical stricture is suspected. Because of the

rapid growth of tumor in patients with recurrence, the hospitalization and recovery time from a surgical

bypass is usually not justified for recurrences resulting in biliary obstruction.

The routine follow-up of a patient after resection of gallbladder cancer includes office visits every 3

months with physical examination and measurement of liver function tests, and cross-sectional imaging

every 3 to 6 months for the first 2 years. In patients who remain free of disease at 2 years, follow-up

should be continued on an individualized basis. Although CA19-9 may be elevated in patients with

gallbladder cancer, the sensitivity and specificity are poor and, thus, should not be used for screening

patients for recurrence.63 If recurrence is identified, systemic therapy with gemcitabine and cisplatin

should be considered as it has been shown to prolong survival in the setting of metastatic disease.64 For

patients who cannot tolerate this regimen, alternatives include single-agent gemcitabine or gemcitabine

plus capecitabine.65

Issues for the Future

Clearly, improving our ability to recognize early gallbladder cancer in high-risk geographic areas would

have an important impact on outcome in these patients. This will likely require implementation of

screening programs in high-risk areas, which could result in prophylactic cholecystectomy.66

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Additionally, standardization of minimum pathologic assessment of gallbladder specimens in high-risk

areas is important to allow for accurate diagnosis, staging, and treatment of patients.

Further studies on characterization of molecular aberrations in gallbladder cancer by next generation

sequencing and other technologies may lead to the discovery of targetable mutations and lead to the

development of novel therapies. Additionally, there is a theoretical role for neoadjuvant therapy for

patients with locoregionally advanced gallbladder cancer given their poor prognosis following surgery.

Clinical trials in this area are needed.

BILE DUCT CARCINOMA

Bile duct carcinomas may arise within the liver (intrahepatic cholangiocarcinoma [ICC] or peripheral

cholangiocarcinoma), at the liver hilum (hilar cholangiocarcinoma or Klatskin tumor), or in the

extrahepatic bile duct (extrahepatic cholangiocarcioma [ECC]). While all arise from the biliary

epithelium, the location of these tumors affects prognosis as well as the potential for curative resection.

Resection of biliary neoplasms, particularly hilar cholangiocarcinoma, often requires radical

resections and complex biliary reconstructions that should be performed only at high-volume,

experienced centers. There is also a role for surgery in palliation for these cancers by providing biliary

bypass for jaundiced patients with unresectable tumors. Because disease is often diagnosed late in the

course and because complex operative techniques are required for potentially curative resection, these

tumors represent one of the greatest challenges for definitive treatment. Adding to this is that there are

no proven effective options for adjuvant therapy.

INCIDENCE

The incidence of ICC in the United States is approximately 0.7/100,000 with a similar mortality. During

the last 30 years, it appears that both the incidence and mortality in the United States are increasing.64

The overall incidence of hilar cholangiocarcinoma, the most common type, is 1.0/100,000 per year in

the United States, although rates are higher in other geographic regions such as Israel and Japan.68

Recent population studies have noted a trend toward a relative increased incidence of ICC compared to

ECC.4,69,70 Using the Surveillance, Epidemiology and End Results-Medicare databases, Welzel et al.70

noted HCV infection, chronic nonalcoholic liver disease and obesity, and smoking being associated only

with ICC and not ECC, possibly explaining the divergent trends in incidence. Cholangiocarcinomas arise

slightly more often in males, with a male-to-female ratio of 1.3:1 and an average age of 50 to 70 years.

Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis,

choledochal cysts, and biliary tract infection, either with Clonorchis or in chronic typhoid carriers.71

Some industrial chemicals (e.g., nitrosamines, dioxin, asbestos, and polychlorinated biphenyls) have also

been implicated in the pathogenesis of cholangiocarcinoma. Although there has been some suggestion of

an increased risk of cholangiocarcinoma arising after transduodenal sphincteroplasty,72 it is difficult to

determine if this is caused by the surgical intervention or the underlying disease leading to

sphincteroplasty.

Pathology and Staging

More than 90% of these bile duct cancers are adenocarcinomas. They are morphologically described as

nodular, which is the most common, scirrhous, diffusely infiltrating, or papillary. Histologic subtypes

include acinar, ductular, trabecular, alveolar, and papillary. Papillary tumors have an improved

outcome. Much less common types of bile duct tumors include cystadenocarcinomas,

hemangioendotheliomas, and mucoepidermoid carcinomas.

STAGING

Table 63-5 American Joint Committee on Cancer, 7th Edition, Staging System for

Perihilar Bile Duct Carcinoma

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In patients with ICC, negative prognostic signs include vascular invasion, multiple tumors, and lymph

node metastases, but not tumor size.73 These tumors can be sclerotic, masslike, or cystic lesions.

Historically, ECCs have been classified according to their location in the upper (60%), middle (15% to

20%), or lower third (15% to 20%) of the bile duct. Middle-third lesions arise between the cystic duct

and the superior border of the duodenum. Lower-third lesions are found below the superior border of

the duodenum but above the ampulla. The problem with this classification is that the anatomic

landmarks are somewhat arbitrary and not clinically useful. Most mid–bile duct malignant obstructions

are caused by gallbladder cancer. A more useful classification is to divide these lesions into upper-half

or lower-half tumors, based on the location of the cystic duct as it enters the common duct (in the case

of normal anatomy). The usefulness of this classification scheme is that it allows the surgeon to

delineate whether a hepatic or pancreatic resection will be required for clearance of tumor. The AJCC

TNM staging system (seventh edition) for bile duct cancers is described in Tables 63-5 and 63-6.

Other staging systems have been created that attempt to incorporate clinically important indicators of

resectability for hilar cholangiocarcinoma that are defined preoperatively, including hepatic lobe

atrophy or portal vein involvement.74 With the increasing acceptance of major hepatic resection for

these tumors, this preoperative staging system attempts to define whether there is ipsilateral

involvement alone, because tumors with bilateral extension past the primary biliary radicles are not

resectable.

STAGING

Table 63-6 American Joint Committee on Cancer, 7th Edition, Staging System for

Distal Bile Duct Carcinoma

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Clinical Findings and Diagnosis

The presentation of patients with cholangiocarcinoma is variable. Patients with hilar or extrahepatic

tumors most commonly present with painless jaundice. Symptoms of mild right upper quadrant pain,

pruritus, anorexia, malaise, and weight loss may also be reported. Cholangitis is the presenting

symptom in 10% to 30% of patients. Some patients, particularly those with ICC may be asymptomatic

and have their tumors discovered incidentally or on evaluation for elevations of alkaline phosphatase

and gamma-glutamyl transferase. Many of these patients will present to the surgeon with a biopsy

showing adenocarcinoma without a known primary tumor. The standard evaluation in these patients

should include tumor markers to rule out an elevated carcinoembryonic antigen (CEA) or α-fetoprotein

(AFP); upper and lower endoscopy to evaluate for a gastrointestinal source; CT scan to assess for a

primary tumor in the gastrointestinal tract or pancreas; and, in women, a mammogram. If no site of

primary disease is found, in most patients, the diagnosis is ICC.

Various imaging tests are available to assess patients with cholangiocarcinoma. Abdominal ultrasound

is noninvasive, easily available, and inexpensive, and thus is commonly used as a first imaging

modality. It can establish the level of biliary obstruction and rule out other etiologies, such as

choledocholithiasis. On CT, cholangiocarcinomas most often appear as hypodense masses with irregular

margins on precontrast phase images, with peripheral rim enhancement on arterial phase, followed by

progressive hyperattenuation on venous and delayed phases.75 Intrahepatic lesions often exhibit

associated capsular retraction and segmental/lobar atrophy and ductal dilatation. Hilar and proximal

extrahepatic lesions demonstrate dilated intrahepatic biliary ducts with a normal, collapsed gallbladder,

and, depending on the level of the tumor, a nondilated or partially dilated extrahepatic biliary tree (Fig.

63-5). While conventional CT is useful for assessment for extrahepatic, metastatic disease and perihilar

adenopathy, high-resolution CT and/or MRI are required for accurate assessment of the tumor and for

determination of respectability (Figs. 63-6 and 63-7).75 Portal vein patency can be determined with

ultrasound, CT, or MRI. Particularly for hilar tumors, signs of hepatic lobar atrophy should be carefully

sought, because this indicates ipsilateral portal vein involvement by tumor. MRCP offers the potential

of evaluating parenchymal, vascular, biliary, and nodal involvement with a single noninvasive

examination.25,27,76

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