Bethesda Handbook of Clinical Oncology, 2nd Edition

Digestive System

6

Biliary Tract Cancer

Gregory D. Leonard*

Eileen M. O'Reilly

Carmen J. Allegra

*The Royal College of Physicians, Dublin, Ireland

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Network for Medical Communication and Research Atlanta, Georgia

Carcinomas of the biliary tract include those cancers arising either in the gallbladder or the bile duct. There were estimated to be 6,800 new cases of gallbladder and biliary tract cancers (excluding intrahepatic biliary tract cancer) and 3,500 deaths from these cancers in 2003 (1). Gallbladder cancer is twice as common as cholangiocarcinoma. The term cholangiocarcinoma was initially used to designate tumors of the intrahepatic bile ducts, but, more recently, it refers 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 gallbladder is 1.2 per 100,000 population in the United States from 1996 to 2000 (http://www.seer.cancer.gov/csr/1975_2000/).
  • 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). The highest incidence 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, 65% 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.
  • Infection:Salmonella typhi, Escherichia coli, and Helicobacter pylori infections 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 pathological finding and can be associated with carcinoma in less than 20% of patients.
  • 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

  • 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% to 20%)
  • Courvoisier 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

  • 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.
  • Plain radiograph of the abdomen may detect calcifications from porcelain gallbladder.
  • Ultrasound is usually abnormal (thickened wall, mass, and loss of gallbladder or liver interface) but may not be specific for gallbladder cancer.
  • Computerized tomography (CT) scan gives better visualization of the extent of tumor growth and nodal status and is useful in 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, and carcinoid carcinoma.

Staging

  • Gallbladder cancers have been classified by Nevin et al. (3) or by using the TNM staging system (4) (see 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.

TABLE 6.1. Staging Systems for Gallbladder Cancer AJCC 6th Edition TNM Stage

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

Treatment

Surgery

  • Only 10% to 30% of patients can be considered for potentially curative surgery (2).
  • 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

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resection of segments V and IVB of the liver (some physicians advocate pancreaticoduodenectomy) (5).

  • 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 improvements in survival in patients reoperated with a radical procedure compared to those receiving only a simple cholecystectomy (6).
  • Some authors have reported extended survivals with radical surgery even in stage IV patients studied by Nevin et al. (7).

TABLE 6.2. Treatment and 5-year Survival of Gallbladder Cancers According to Stage

TNM stage

Treatment

Median survival

5-yr 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

Radiation

  • In patients with unresectable tumors, radiation alone is rarely a successful palliative procedure (8).
  • 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.

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Chemotherapy and Palliation

The benefits and options available for chemotherapy and palliation of carcinoma of the gallbladder are the same as those for cholangiocarcinoma and are discussed in the sections Chemotherapy and Palliation.

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

  • Cholangiocarcinoma is subdivided into proximal extrahepatic (perihilar or Klatskin tumor; 50% to 60%), distal extrahepatic (20% to 25%), intrahepatic (peripheral tumor; 20% to 25%), and multifocal (5%) tumors (9).
  • 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. The incidence has increased, partly because of increased recognition of the intrahepatic form of the disease.
  • Cholangiocarcinoma is more common in men (10).

Etiology

  • Inflammatory conditions:Primary sclerosing cholangitis is associated with a 5% to 15% lifetime risk. Ulcerative colitis and chronic intraductal gallstone disease also increase risk.
  • 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.
  • Miscellaneous:Smoking, thorotrast (a radiologic contrast agent), asbestos, radon, and nitrosamines are also known to increase risk (5).

Clinical Features

  • Intrahepatic cholangiocarcinoma may present as a mass, be asymptomatic, or produce vague symptoms such as pain, anorexia, weight loss, night sweats, and malaise.
  • 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

  • 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).
  • 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.
  • CT scan is better at defining anatomy and can be used to direct CT scan–guided biopsies.
  • MRCP is the optimal imaging modality.

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  • 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.
  • The diagnosis of cholangiocarcinoma is frequently made on the basis of 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.

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 (11).
  • Staging is based on the TNM classification (4). Other classifications such as the classification by Bismuth et al. (12) define the extent of ductal involvement (Table 6.3).

TABLE 6.3. Staging systems for Extrahepatic Bile Duct Cancers AJCC 6th Edition TNM Classification

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

T1–3 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

Intrahepatic cancers are classified as per liver tumors

Ampulla of Vater cancers have a separate staging classification (4)

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

Treatment

Surgery

  • Surgery is the only curative option and may be possible in 30% to 60% of patients (10). 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 (see Table 6.4).
  • Long-term survival has been reported after liver transplantation in three studies, but transplantation is not a standard approach (5).

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TABLE 6.4. Treatment and Survival of Cholangiocarcinomas According to Location

Location

Treatment

Median survival

5-yr survival (%)

Extrahepatic (hilar)

Type I + II

12–24 mo

   9–18

En bloc resection of extrahepaticbile ducts, gallbladder, regionallymphadenectomy, and Roux-en-Y hepaticojejunostomy

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

Radiation

  • In patients with unresectable disease, 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 (13).
  • Adjuvant radiation is not recommended because there is limited and conflicting data on this subject. One retrospective series reported a significant improvement in 5-year survival for those treated with radiation therapy and surgery compared to surgery alone (39% versus 13%) (14). However, the mortality with surgery in the surgery alone group was 10%.

Chemotherapy

  • Chemotherapy appears to provide palliative benefit to patients with biliary tract cancer, although definitive proof of a survival benefit is lacking (15).
  • There are now many chemotherapy options for cholangiocarcinoma and gallbladder cancer (5,16). 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 as the 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, but as yet there have been no randomized comparisons showing clear-cut superiority over single-agent therapy.
  • Mitomycin, as a single-agent or as 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.

Palliation

  • Patients with unresectable or metastatic disease may benefit from palliative surgery, radiation, or 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

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(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).

  • Celiac plexus block or photodynamic therapy are other options (17).

REFERENCES

  1. Jemal A, Murray T, Samuels A, et al. Cancer Statistics, 2003. CA Cancer J Clin2003;53:5–26.
  2. Misra S, Chaturvedi A, Misra NC, et al. Carcinoma of the gallbladder. Lancet Oncol2003;4:167–176.
  3. Nevin JE, Moran TJ, Kay S, et al. Carcinoma of the gallbladder, staging, treatment and prognosis. Cancer1976;37:141–148.
  4. American Joint Committee on Cancer. Cancer staging manual, 6th ed. New York: Springer-Verlag, 2002:139–156.
  5. Yee K, Sheppard BC, Domreis J, et al. Cancers of the gallbladder and biliary ducts. Oncology2002;16:939–957.
  6. Todoroki T, Kawamoto T, Takahashi H, et al. Treatment of gallbladder cancer by radical resection. Br J Surg1999;86:622–627.
  7. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg2000;232:557–569.
  8. Houry S, Haccart V, Huguier M, et al. Gallbladder cancer: role of radiation therapy. Hepatogastroenterology1999;46:1578–1584.
  9. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut2002;51(Suppl. VI):vi1–vi9.
  10. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med1999;341:1368–1378.
  11. Corvera CU, Weber SM, Jarnagin WR. Role of laparoscopy in the evaluation of biliary tract cancer. Surg Oncol Clin North Am2002;11:877–891.
  12. Bismuth H, Castaing D, Traynor O, et al. Resection or palliation: priority of surgery in the treatment of hilar cancer. World J Surg1988;12:39–47.
  13. Morganti AG, Trodella L, Valentini V, et al. Combined modality treatment in unresectable extrahepatic biliary carcinoma. Int J Radiat Biol Phys2000;46:913–999.
  14. Todoroki T, Ohara K, Kawamoto T, et al. Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Biol Phys2000;46:581–587.
  15. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced biliary and pancreatic cancer. Ann Oncol1996;7(6):793–600.
  16. Henja M, Pruckmayer M, Raderer M. The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer1998;34:977–986.
  17. Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology2000;31:291–298.