Carcinomas of the biliary tract include those cancers arising in either the gallbladder or the bile duct. There were estimated to be 9,250 new cases of gallbladder and biliary tract cancers (excluding intrahepatic biliary tract cancer) and 3,340 deaths from these cancers in 2006 (
1). Gallbladder cancer is twice as common as cholangiocarcinoma. The term cholangiocarcinoma was initially used to designate tumors of the intrahepatic bile ducts; it is now taken to refer to the entire spectrum of tumors arising in the intrahepatic, perihilar, and distal bile ducts. The epidemiology, clinical features, staging, and surgical treatment are distinct for carcinomas arising in the gallbladder and bile duct, and these are described separately. The palliative treatment options are similar and are discussed together at the end of the chapter.
CARCINOMA OF THE GALLBLADDER
Epidemiology
The age-adjusted incidence of carcinoma of the gallbladder is 1.2 per 100,000 population in the United States from 2000 to 2004 (http://seer.cancer.gov/csr/1975_2004/).
Carcinoma of the gallbladder is the fifth most common GI malignancy.
It affects women two to six times more commonly than men and has a 50% greater incidence in whites as compared to black individuals (2). There is a prominent geographic variation in the incidence of gallbladder cancer, and the highest is among Native Americans and in South America (particularly Chile), Japan, and Eastern Europe, and the lowest incidence is in Singapore, Nigeria, and the United States.
The mean age at diagnosis of the carcinoma is 65 years.
Etiology
Cholelithiasis (gallstones): Of patients with gallbladder carcinoma, 70% to 90% have gallstones, whereas only 1% to 3% of patients with gallstones develop gallbladder cancer. The risk increases with increase in size of the stones (2).
Infection: Chronic infection with Salmonella typhi, Escherichia coli, and Helicobacter pylori may also cause gallbladder carcinomas.
Gallbladder polyps or porcelain gallbladder: Polyps >1 cm diameter have the greatest malignancy potential. Porcelain gallbladder due to extensive calcium deposition in the wall is a pathologic finding and is associated with cholelithiasis in nearly all cases. The reported incidence of gallbladder cancer in patients with this condition ranges from 12.5% to 60%.
Miscellaneous: Anomalous pancreaticobiliary duct junction resulting in backflow of pancreatic juice and biliary stasis may cause gallbladder cancer. Obesity, estrogens, and chemicals from the rubber industry have also been associated with this disease.
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Clinical Features Early disease may be asymptomatic or present with very nonspecific symptoms, including the following:
Pain (82%)
Weight loss (72%)
Anorexia (74%)
Nausea or vomiting (68%)
Mass in the right upper quadrant (65%)
Jaundice (44%)
Abdominal distension (30%)
Pruritus (20%)
Incidental (15-20%)
Courvoisier’s law states that if the gallbladder is enlarged and if the patient has painless jaundice, the cause is unlikely to be gallstones.
In elderly patients, gallbladder cancer may present as cholecystitis.
Diagnosis
The majority of gallbladder cancers are diagnosed as an incidental finding during exploration of presumed benign disease. Approximately 1% to 2% of patients undergoing exploration of presumed benign disease will have gallbladder cancer.
Ultrasound is usually abnormal (thickened wall, mass, and loss of gallbladder or liver interface) but may not be specific for gallbladder cancer.
Plain radiograph of the abdomen may detect calcifications from porcelain gallbladder.
Endoscopic ultrasound (EUS) is more accurate than transabdominal ultrasound; it is useful in differentiating polyps from cancer and also in preoperative staging as it provides information on depth of tumor invasion and on regional lymph node appearance. It is however highly operator dependent and not available in all centers (3).
Laboratory studies are generally not diagnostic but abnormal serology can occur with elevations in levels of alkaline phosphatase, γ-glutamyl transpeptidase, bilirubin, carcinoembryonic antigen (CEA), or CA 19-9, but these factors are more commonly elevated in cholangiocarcinoma.
Computerized tomography (CT) scan allows visualization of the extent of tumor growth and nodal status and is useful in radiological staging of gallbladder cancer where distant metastases are common.
Magnetic resonance cholangiopancreatography (MRCP) and cholangiography by endoscopic retrograde cholangiopancreatography (ERCP) are the optimal imaging modalities to outline local anatomy for preoperative planning (2).
Biopsies prior to surgery may result in tumor seeding; therefore, the diagnosis is usually made at the time of surgery.
Pathology
Adenocarcinoma accounts for more than 85% of cases. It is subcharacterized into papillary, tubular, mucinous, or signet cell type. Other histologies include anaplastic, squamous cell, small cell, carcinoid, and lymphoma.
Staging
Gallbladder cancers are classified by Nevin et al. (4) or by using the TNM staging system (5) (Table 6.1).
A staging laparoscopy is a useful adjunct to imaging modalities because it may detect intra-abdominal metastases, thereby sparing radical and potentially morbid surgery in patients.
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| TABLE 6.1. TNM Staging systems for gallbladder cancer |
| Stage IA | T1 N0 M0 | T1a: invades lamina propria
T1b: invades the muscle layer | | Stage IB | T2 N0 M0 | T2: invades perimuscular connective tissue | | Stage IIA | T3 N0 M0 | T3: perforates the serosa and/or directly invades the liver or one other adjacent organ | | Stage IIB | T1-3 N1 M0 | N1: metastases in cystic duct, choledochal, and/or hilar lymph nodes | | Stage III | T4 N0-1 M0 | T4: tumor invades portal vein or hepatic artery or multiple extrahepatic organs or structures Stage IV Any T any N M1 M1: distant metastases | | Nevin stage | | Stage I | Intramucosal only | | | Stage II | Extends to muscularis | | | Stage III | Extends through serosa | | | Stage IV | Transmural involvement and cystic lymph nodes are involved | | | Stage V | Direct extension to liver or distant metastases | | | Source: AJCC Cancer Staging Manual, 6th ed., 2002. |
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Treatment Surgery
Surgery is the only potentially curative therapy.
Only 10% to 30% of patients can be considered for potentially curative surgery (2).
Contraindications to surgery include liver or peritoneal metastases, ascites, extensive involvement of the hepatoduodenal ligament, and encasement or occlusion of major vessels. Direct involvemt of adjacent organs is not an absolute contraindication.
Surgery can be a simple cholecystectomy or a radical (extended) cholecystectomy.
A radical procedure involves wedge resection of the gallbladder bed, excision of the supraduodenal extrahepatic bile duct, en bloc dissection of regional lymph nodes, and resection of segments V and IVB of the liver (some physicians advocate pancreaticoduodenectomy) (6).
Stage I disease can be treated successfully with a simple cholecystectomy, with survival rate being greater than 85%, but some physicians advocate radical surgery (Table 6.2).
Up to 40% of stage IIA (formerly stage II) cancers are found to have lymph node involvement at surgery, upstaging them to pathological stage IIB (formerly stage III). Because of this upstaging, most surgeons advocate radical surgery for stage II and above. Many studies have demonstrated
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improvements in survival in patients reoperated with a radical procedure compared to those receiving only a simple cholecystectomy (7).
Some authors have reported extended survivals with radical surgery even in stage IV patients studied by Nevin et al. (8).
| TABLE 6.2. Treatment and 5-year survival of gallbladder cancers according to stage |
| TNM stage | Treatment | Median survival | 5-year survival (%) | | I | Simple cholecystectomy | 19 mo | 60-100 | | Radical cholecystectomy | | | | II | Radical cholecystectomy | 7 mo | 10-20 | | +/− Radiation therapy (not standard) | | | | III | Radical cholecystectomy | 4 mo | 5 | | +/− Radiation therapy (not standard) | | | | IV | Palliation with stent placement | 2 mo | 0 | | Surgery or radiation or chemotherapy or combination of these | | |
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Radiation
In patients with unresectable tumors, radiation alone is rarely a successful palliative procedure (9).
A number of reports have documented improvements in survival rates in cases of intraoperative or postoperative adjuvant radiotherapy. No prospective randomized controlled trials have been performed to address this issue.
Chemotherapy and Palliation The benefits and options available for chemotherapy and palliation of carcinoma of the gallbladder are the same as those for cholangiocarcinoma. Survival The various aspects of survival following treatment of gallbladder cancers according to stage are given in
Table 6.2. CARCINOMA OF THE BILE DUCTS (CHOLANGIOCARCINOMA) Epidemiology
Cholangiocarcinomas arise from the epithelial cells of the intrahepatic and extrahepatic bile ducts.
Cholangiocarcinoma accounts for 3% of all GI malignancies (9).
Cholangiocarcinoma is subdivided into proximal extrahepatic (perihilar or Klatskin tumor; 50-60%), distal extrahepatic (20-25%), intrahepatic (peripheral tumor; 20-25%), and multifocal (5%) tumors (10).
The incidence of intrahepatic bile duct tumors was 0.9 cases per 100,000 population between 1996 and 2000, and for other biliary tumors was 1.5 cases per 100,000 population. For unclear reasons the incidence of intrahepatic cholangiocarcinoma has increased, but this may be because of increased recognition.
The incidence increases with age and is more common in men (11).
Etiology
Inflammatory conditions: Primary sclerosing cholangitis is associated with a 10% to 15% lifetime risk. Ulcerative colitis and chronic intraductal gallstone disease also increase risk. Nearly 30% of cholangiocarcinomas are diagnosed in patients with coexistent ulcerative colitis and primary sclerosing cholangitis.
Bile duct abnormalities: Caroli disease (cystic dilatation of intrahepatic ducts), bile duct adenoma, biliary papillomatosis, and choledochal cysts increase risk.
Infection: In Southeast Asia, risk can be increased 25- to 50-fold by parasitic infestation from Opisthorchis viverrini and Clonorchis sinensis. Hepatitis C cirrhosis is also a risk factor.
Genetic: Lynch syndrome II and multiple biliary papillomatosis are associated with an increased risk of developing cholangiocarcinoma.
Miscellaneous: Smoking, thorotrast (a radiologic contrast agent), asbestos, radon, and nitrosamines are also known to increase risk (6).
Clinical Features Cholangiocarcinomas usually become symptomatic when the biliary system becomes blocked.
Intrahepatic cholangiocarcinoma may present as a mass, be asymptomatic, or produce vague symptoms such as pain, anorexia, weight loss, night sweats, and malaise.
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Extrahepatic cholangiocarcinoma usually presents with symptoms and signs of cholestasis (icterus, pale stools, dark urine, and pruritus or cholangitis, which includes pain, icterus, and fever).
Diagnosis The diagnosis of cholangiocarcinoma can be challenging.
Ultrasonography is the first-line investigation for suspected cholangiocarcinoma. Biliary dilatation is usually seen. This technique can often overlook masses and is poor at delineating anatomy.
ERCP provides anatomical information (cholangiography) that is useful for planning surgery, but, more importantly, it may provide a tissue diagnosis. However, because these tumors are desmoplastic, cytology brushings have a low yield (30%) in making the diagnosis. When brushings and biopsy are combined, the yield improves to 40% to 70%. Endoscopic ultrasound and positron emission tomography (PET) may provide further information on local and distant disease, respectively.
Endoscopic ultrasound may be useful in visualizing the extent of tumor and lymph node involvement of distal bile duct lesions. Its role in proximal bile duct lesions is less clear
A cholestatic serologic picture (as discussed in gallbladder cancer) may be seen. A value of CA 19-9 >100 U per mL is highly suggestive of malignancy and is elevated in up to 85% of patients with cholangiocarcinoma (9).
CT scan defines anatomy and can be used to direct CT scan-guided biopsies.
MRCP is the optimal imaging modality.
The diagnosis of cholangiocarcinoma is frequently based on the clinical scenario, serology, and radiology but without histologic confirmation, but such a diagnosis in the absence of tissue should be made only after efforts are taken to prove the diagnosis by use of cytologic or pathologic evaluation preoperatively.
Pathology
Adenocarcinomas account for 95% of tumors. They are graded as well, moderately, and poorly differentiated and are further divided into sclerosing, nodular, and papillary subtypes.
Staging
Up to 50% of patients have lymph node involvement at presentation and 10% to 20% have peritoneal involvement. In one series, laparoscopy prevented unnecessary surgery in one-third of patients (12).
Staging is based on the TNM classification (5). Other classifications such as the classification by Bismuth et al. (13) define the extent of ductal involvement (Table 6.3).
| TABLE 6.3. Staging systems for extrahepatic bile duct cancers |
| Stage IA | T1 N0 M0 | T1: tumor confined to the bile duct | | Stage IB | T2 N0 M0 | T2: tumor invades beyond the bile duct wall | | Stage IIA | T3 N0 M0 | T3: tumor invades liver, gallbladder, pancreas, unilateral branches of portal vein, or hepatic artery | | Stage IIB | T1-T3 N1 M0 | N1: regional lymph node | | Stage III | T4 any N M0 | T4: tumor invades main portal vein or bilateral branches, common hepatic artery, or other adjacent structures | | Stage IV | Any T any N M1 | M1: distant metastases | | Bismuth classification | | Type I | Tumors below the confluence of left and right hepatic ducts | | | Type II | Tumors reaching the confluence but not involving the left or right hepatic ducts | | | Type III | Tumors occluding the common hepatic duct and either the right or left hepatic duct | | | Type IV | Tumors that are multicentric or that involve the confluence of the right and left hepatic ducts | | | Source: AJCC Cancer Staging Manual, 6th ed., 2002. |
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Treatment Surgery
Surgery is the only curative option and may be possible in 30% to 60% of patients (14). The goals of surgery are (a) tumor removal and (b) establishing or restoring biliary drainage.
Surgery for extrahepatic hilar cholangiocarcinomas is based on the stage of disease, and the goal of surgical intervention is to obtain a tumor-free margin >5 cm (Table 6.4).
Long-term survival has been reported after liver transplantation in three studies, but transplantation is not a standard approach (6).
Trimodality therapy is also advocated by some groups.
Radiation/Chemoradiation
In patients with unresectable locally advanced disease or resected disease with positive margins there have been reports of long-term survival with combined-modality chemoradiotherapy. One report documented a median survival of 21 months in patients with unresectable cancer or those with residual disease after surgery (15,16).
Definitive evidence from phase 3 studies to support this practice, however, remains lacking.
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In locally advanced disease radiation with or without chemotherapy may ameliorate painful symptoms and contribute towards biliary decompression.
Adjuvant radiation is not a standard recommendation because there is limited and conflicting data on this subject.
| TABLE 6.4. Treatment and survival of cholangiocarcinomas according to location |
| Location | Treatment | Median survival | 5-year survival (%) | | Extrahepatic (hilar) | Type I + II: en bloc resection of extrahepatic bile ducts, gallbladder, regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy | 12-24 mo | 9-18 | | Type III: as above plus right/left hepatectomy | | | | Type IV: as above plus extended right/left hepatectomy | | | | Extrahepatic (distal) | Pancreaticoduodenectomy | 12-24 | mo 20-30 | | Intrahepatic | Resect involved segments or lobe of liver | 18-30 mo | 10-45 |
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Chemotherapy
Chemotherapy appears to provide palliative benefit to patients with biliary tract cancer, although definitive proof of a survival benefit is lacking (17). Similarly, its role in the adjuvant setting is uncertain.
Many trials supporting the use of chemotherapy in biliary cancer contain small numbers of patients and include a heterogeneous mix of bile duct tumors, gallbladder cancer, pancreatic cancer, and hepatic cancer.
There are now many chemotherapy options for cholangiocarcinoma and gallbladder cancer (6,18). Many of these trials are reported in abstract form or sample sizes are small, so the treatment of choice has not been established. Usual response rates are between 10% and 20%, and high response rates found in single-institution studies have not been reproducible in larger multi-institution trials.
Historically, fluoropyrimidines have been the cytotoxic therapy of choice, but the likelihood of response is less than 10%. Increasingly, gemcitabine is considered a standard of care.
Gemcitabine combinations, for example, cisplatin and gemcitabine, have demonstrated high response rates of 20% to 60% and median survival up to 20 months. Gemcitabine combined with capecitabine is a frequently used regimen (19,20) but as yet, there have been no randomized comparisons showing clear-cut superiority over single-agent therapy.
Other gemcitabine combinations that have demonstrated efficacy in the treatment of advanced biliary tumors are oxaliplatin and irinotecan.
Mitomycin, as a single agent or in combination therapy, has demonstrated response rates of up to 47% and median survivals of 9.5 months.
Other single agents with activity include docetaxel, irinotecan, raltitrexed, anthracyclines, carboplatin, and oxaliplatin.
Targeted Therapy
A phase 2 study has shown erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor to have efficacy in a small study of previously treated and chemo-naive patients with biliary cancer (21).
Antitumor activity was also noted in a small phase 2 trial combining erlotinib with bevacizumab the monoclonal antibody directed against the vascular endothelial growth factor (22). Similarly small trials have also combined targeted therapy with chemotherapy (23). Clinical trials are ongoing to investigate this area.
Palliation
Patients with unresectable or metastatic disease may benefit from palliative surgery, radiation, chemotherapy, or a combination of these.
Biliary drainage can be achieved by Roux-en-Y choledochojejunostomy, bypass of the site of obstruction to left or right hepatic duct, or endoscopic or percutaneously placed stents (metal-wall stents have a larger diameter and are less prone to occlusion or migration and are preferably used in patients with a life expectancy of greater than 6 months and/or in those who have unresectable disease).
Photodynamic therapy is another option for patients with locally advanced inoperable disease (24). This involves injecting a porphyrin photosensitizer and then endoscopically applying light to the tumor. Although the data are derived from small studies to support this practice, the survival benefit derived from photodynamic therapy appears impressive with one report showing an improvement in median survival of 14 months (25).
Celiac plexus blockade may also ameliorate symptoms of pain in the patient with inoperable disease.
