Gallbladder Cancer

Synonyms and related keywords: biliary cancer, biliary tract cancer, cancer of the biliary tree, gallbladder cancer, gallstones, chronic typhoid infections, abnormal pancreaticobiliary duct junctions, inflammatory bowel disease, polyposis coli, cholangiocarcinomas


INTRODUCTION

Background: Cancers of the biliary tract include cholangiocarcinomas (cancers arising from the bile duct epithelium) and gallbladder cancers. Both types of biliary tract cancers are rare and have an overall poor prognosis. They also both present difficulties in diagnosis. These diseases are often discussed together and are co-mingled in therapeutic trials. However, this leads to significant confusion. Despite some similarities, gallbladder cancer is a distinct clinical entity from cholangiocarcinoma and will be discussed separately in this article.

Pathophysiology: Gallbladder cancer arises in the setting of chronic inflammation. In the vast majority of patients (>75%), the source of this chronic inflammation is gallstones. Other more unusual causes of chronic inflammation are also associated with gallbladder cancer. These causes include patients with chronic typhoid infections, abnormal pancreaticobiliary duct junctions, inflammatory bowel disease, or polyposis coli.

Chronic gallbladder inflammation is likely only part of the cause of the malignant transformation seen in gallbladder cancer. Ingestion of certain medications (oral contraceptives, INH, and methyldopa) as well as certain occupational chemical exposures may play a significant contributing role. The role of various oncogenic mutations in gallbladder cancer is an area of active research.

Gallbladder cancer incidence increases with age and is more common in women.

The tumor is usually located in the fundus of the gallbladder. Local spread through the gallbladder wall can lead to direct liver invasion, or, if in the opposite direction, leads to transperitoneal spread (20% of patients at presentation), with implants on the liver, on the bowel, and in the pelvis. Tumor may also directly invade other adjacent organs such as the stomach, duodenum, colon, pancreas and extrahepatic bile duct. At diagnosis, the gallbladder is often replaced or destroyed by the cancer, and approximately 50% of patients have regional lymph node metastases.

Frequency:

• In the US: Approximately 6000 new cases of gallbladder cancer are diagnosed in the United States annually. According to the 2001 United States Cancer Statistics, the highest incidence rates for gallbladder cancer are found among the Hispanic population. The incidence rates for Hispanic males is 1.5 cases per 100,000, and, for Hispanic females, it is 2.9 cases per 100,000. This compares to an incidence rate of 0.8 per 100,000 for white males and 1.4 per 100,000 for white females. African Americans and Asians have an intermediate incidence.

  Gallbladder cancer causes about 2800 deaths per year in the United States.

• Internationally: Considerable variation exists in the incidence of gallbladder cancer throughout the world. Areas with high incidence rates include Chile, Bolivia, Israel, and Japan. Spain and India have low incidence rates.

Mortality/Morbidity: Survival is correlated with staging based on the American Joint Committee on Cancer (AJCC) tumor, node, metastases (TNM) staging system.

Patients with stage IA disease (T1N0M0) should be cured with a simple cholecystectomy. In selected surgical series, patients with stage IB (T2N0M0) disease treated with extended cholecystectomy have a 5-year survival rate of 70-90%, and patients with stage IIB (T1-3N1M0) treated with extended cholecystectomy have a 5-year survival of 45-60%. Stage III (T4, any N,M0) gallbladder cancer is generally not surgically curable. The 1-year survival rate for advanced gallbladder cancer is less than 5%. The median survival is 2-4 months.

The SEER registry from 1995-2001 shows 5-year survival rates for localized gallbladder cancer of approximately 40%. The 5-year survival rate for regional disease is approximately 15%, and the 5-year survival rate for distant metastatic disease is less than 10%.

Unfortunately, only about 10-20% of patients present with tumor confined to the gallbladder wall. At diagnosis, 40-60% of patients have lesions that perforate the gallbladder wall and invade adjacent organs (T3) and 45% of patients have regional lymph node involvement (N1). Approximately 30% of patients present with metastatic disease.

Race: The highest rates of gallbladder cancer are found in the US Native American and Hispanic populations, and in South America, Israel, and Japan.

Sex: A substantial female predominance exists worldwide, with female-to-male ratios of approximately 2.5:1-3:1.

Age: Gallbladder cancer is most typically diagnosed in the seventh decade, with a median age of 62-66 years.

CLINICAL

History: The symptoms of gallbladder cancer overlap with the symptoms of gallstones and biliary colic. Abdominal pain may be of a more diffuse and persistent nature than the classic right upper quadrant pain of gallstone disease. Jaundice, anorexia, and weight loss often indicate more advanced disease.

Physical:

• Jaundice

• Palpable mass in the right upper quadrant (Courvoisier sign, if this is due to a palpable gallbladder)

• Periumbilical lymphadenopathy (Sister Mary Joseph nodes)

• Left supraclavicular adenopathy (Virchow node)

• Pelvic seeding: Mass is palpated on digital rectal examination (Blumer shelf)

Causes: See Pathophysiology. Associated conditions include the following:

• Chronic gallstones

• Calcification of the gallbladder (porcelain gallbladder) - 10-25% incidence of gallbladder cancer

• Crohn ileocolitis

• Ulcerative colitis

• Occupational chemical exposure

• Estrogens

• Typhoid carriers

• Anomalous pancreatobiliary duct junction

• Gallbladder polyps

DIFFERENTIALS

Acalculous Cholecystitis
Acalculous Cholecystopathy
Ampullary Carcinoma
Bile Duct Strictures
Bile Duct Tumors
Biliary Colic
Biliary Disease
Biliary Obstruction
Carcinoma of the Ampulla of Vater
Cholangiocarcinoma
Cholangitis
Cholecystitis
Choledochal Cysts
Choledocholithiasis
Cholelithiasis
Clostridial Cholecystitis
Gallbladder Mucocele
Gallbladder Volvulus
Hepatic Carcinoma, Primary
Liver Abscess
Neoplasms of the Endocrine Pancreas
Pancreatic Cancer
Pericholangitis
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis

WORKUP

Lab Studies:

• Tumor marker CA 19-9

• CA 19-9 may be significantly elevated in both cholangiocarcinoma and gallbladder cancer.

• CA 19-9 tests may be helpful in the appropriate situation if the clinical suspicion for gallbladder cancer is high.

• Liver function tests: Elevated alkaline phosphatase and bilirubin levels are often found with more advanced disease.

• BUN, creatinine, UA: Assess renal function prior to performing an enhanced CT scan.

• CBC: Anemia may be an indicator of more advanced disease.

Imaging Studies:

• Ultrasonography (US) is a standard initial study in patients with right upper quadrant pain. A mass can be identified in 50-75% of patients with gallbladder cancer. It also can delineate metastatic lesions in the liver.

• Computed tomography (CT) scans also may be useful in patients with upper abdominal pain and can demonstrate tumor invasion outside of the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis. Liver invasion occurs in 60% of cases, and the combination of CT scan and US provides accurate details of disease extension.

• Magnetic resonance imaging (MRI) has been useful in examining this region for disease extension into other tissues or metastatic disease in the liver. It can provide details of the vasculature for preoperative planning via magnetic resonance angiogram (MRA) and bile duct passages via magnetic resonance cholangiogram (MRCP).

• Cholangiography, via a percutaneous route, or endoscopic retrograde cholangiography (ERCP) may establish the diagnosis of gallbladder cancer by bile cytology.

• Endoscopic ultrasonography can be useful to assess regional lymphadenopathy in conjunction with other studies.

• Angiography may confirm encasement of the portal vein or hepatic artery, and assist in preoperative planning for definitive resection.

• A routine chest radiograph should also be obtained.

Procedures:

• ERCP can demonstrate the site of the obstruction by direct retrograde dye injection, as well as excluding ampullary pathology by endoscopic evaluation. Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histology. Palliative stenting to relieve biliary obstruction can be performed at the time of the evaluation.

• Percutaneous transhepatic cholangiography (PTC) may allow access to the proximal biliary tree that has become obstructed by extensive tumor growth from the gallbladder. Material for cytology can be obtained and drainage performed as well.

• Other methods to obtain tissue include CT or ultrasound needle aspiration, if a mass lesion is present, and endoscopic ultrasonographic (EUS) fine-needle aspiration.

Histologic Findings: Adenocarcinoma is the primary histologic finding in 80-85% of gallbladder carcinomas, with several histologic subtypes, including papillary, nodular, and infiltrative. The papillary type appears to be less aggressive and more often localized and has a better prognosis than the other forms. Additional rare histologic types of gallbladder cancer exist. These include squamous cell cancer, sarcomas, carcinoid, lymphoma, and melanoma.

Grade also is important, with poorly differentiated tumors associated with a poorer prognosis than the typically less infiltrative, better differentiated tumors with metaplasia.

Staging: Staging of tumor extent is essential in selection of the appropriate treatment approach.

The AJCC 6th edition guidelines follow the TNM system, with depth of tumor penetration and regional spread defined pathologically . Survival is correlated directly with stage of disease.

Primary tumor

• Category T

• TX - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ
• T1 - Tumor invades lamina propria or muscle layer
  • T1a - Tumor invades lamina propria
    
  • T1b - Tumor invades muscle layer
• T2 - Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
• T3 - Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts
• T4 - Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures
• Regional lymph node

• Category N

• NX - Regional lymph nodes cannot be assessed
• N0 - No metastases in regional lymph nodes
• N1 - Metastases in regional lymph nodes
• Distant metastases

• Category M

• MX - Presence of metastases cannot be assessed
• M0 - No distant metastases
• M1 - Distant metastases

• TNM Groupings by stage
  • Stage 0 Tis N0 M0
  • Stage IA - T1 N0 M0
  • Stage IB - T2 N0 M0
  • Stage IIA - T3 N0 M0
  • Stage IIB - T1 N1 M0
    • T2N1M0
    • T3N1M0
  • Stage III - T4 any N M0
  • Stage IV - any T any N M1

TREATMENT

Medical Care: Although complete surgical resection is the only therapy to afford a chance of cure, en bloc resections of the gallbladder and portal lymph nodes carry a high morbidity and mortality (similar to bile duct carcinoma). Adequate surgical margins may be difficult to achieve. The role of adjuvant radiation therapy is to control microscopic residual deposits of carcinoma in the tumor bed and regional lymph nodes. The rationale for radiation therapy with or without concurrent chemotherapy in patients with unresectable disease is to provide palliation of symptoms. Rarely it may also increase survival.

• The role of radiotherapy for carcinoma of the gallbladder is unclear because the available literature is derived from small, single institutional experiences over many years, with a variety of treatment methods used. Complicating this is the fact that only approximately 25% of patients with carcinoma of the gallbladder can undergo curative surgery.

• Even large institutions do not accrue more than single-digit numbers of patients per year, and many are not on protocol. Available reports contain small numbers of patients with incomplete reporting of technical treatment data, histological grading, and tumor extent. The literature is strongly biased by patient selection, and interpretation of the reports is difficult. Given these difficulties, the data support the following statements:

• Radiotherapy has been delivered in a variety of situations, including after curative resections with close or positive microscopic margins, gross macroscopic residual disease, and palliative debulking with bypass.

• Significant increases in survival rates have been reported after curative surgery is attempted and only microscopic residual disease remains. Survival in these patients after surgery alone ranges from 6-7 months and can be prolonged to longer than 12 months with external beam radiotherapy administered as adjuvant therapy. This excludes patients with T1 or stage I disease confined to the mucosa of the gallbladder. Their survival rates are extremely high and they are at very low risk for lymph node metastases.

• All patients with tumors beyond the mucosa are candidates for external beam radiotherapy. Patients with curative resection and AJCC stages T2-T4 who have had complete resection who receive radiation have a mean survival of over sixteen months. This is compared to less than 6 months mean survival with surgery alone.

• 5-FU–based chemotherapy is usually given in conjunction with concurrent radiation therapy both in the adjuvant and palliative setting. Other chemotherapy drugs have been tested in unresectable gallbladder cancer with no consistent or significant improvement in the known poor prognosis. These drugs include Adriamycin, mitomycin C, and cis-platinum. Patients with a good performance status should be considered for a clinical trial. Patients with a poor performance status may be best treated with supportive care.

Surgical Care: Complete surgical resection is the only therapy to offer a chance of cure in this disease. Unfortunately, only a minority of patients present with early-stage disease and are, therefore, considered for curative resection.

• Because of the high incidence of gallbladder cancer in a calcified (porcelain) gallbladder, patients with this finding should be strongly considered for an open cholecystectomy even if they are asymptomatic. It is best to avoid a laparoscopic cholecystectomy in this setting to avoid the risk of peritoneal seeding if, indeed, gallbladder cancer is present.

• Gallbladder cancer is sometimes found as an incidental pathology finding after a cholecystectomy is performed for reasons other than cancer. If the tumor is carcinoma in situ (Tis) or only invades the lamina propria (T1a) and the margins of resection are negative, then postoperative observation alone is acceptable. If the tumor is T1b or greater or the margins of resection are positive, then further surgical resection is necessary if no metastatic disease is present on evaluation (CT, MRI, chest radiograph). This additional surgery should include partial hepatic resection and regional lymphadenectomy (porta hepatis, gastrohepatic ligament, and retroduodenal lymph nodes). A bile duct resection may also be necessary depending on tumor size and location. If the original surgery was performed via a laparoscopic approach, then the port sites should also be resected to avoid tumor seeding.

• Patients who present with a gallbladder mass or jaundice are evaluated preoperatively for resectability as previously described. If the tumor is resectable, the patient undergoes a cholecystectomy with en bloc liver resection and regional lymphadenectomy. Bile duct excision may also be necessary (especially if jaundice is present). The operative morbidity and mortality rate increases with the complexity of the operative procedure.

• The surgical role in treatment of unresectable disease is usually limited to biopsy of the tumor for diagnosis and possible biliary decompression procedures.

Consultations: A radiation oncologist and medical oncologist should be part of the multidisciplinary team participating in the treatment of patients with gallbladder cancer.

MEDICATION

Historically, chemotherapy has not shown significant activity in gallbladder carcinoma. Typically, 5-flurouracil (5-FU) has been used with response rates of 10-24% in advanced disease. Often 5-FU is administered either as a bolus or as a prolonged infusion regimen with radiation. Capecitabine is a currently available oral alternative to a prolonged 5-FU infusion.

More recently, gemcitabine has shown activity in gallbladder cancer. Early phase studies show an increased response rate with gemcitabine combination therapy over historical treatment response rates with 5-FU alone. Gemcitabine has been studied in combination with cis-platinum and capecitabine.

Currently, no clearly defined standard exists for chemotherapy in gallbladder cancer. Patients should be encouraged to participate in clinical trials.

FOLLOW-UP

Further Outpatient Care:

• Because survival usually is very short in patients with advanced disease, close follow-up is essential to preserve the best quality of life. For patients with earlier stage disease who are treated with surgery and postoperative radiation therapy and chemotherapy, intermittent posttreatment imaging studies can be considered (particularly in the first few years).

• Hospice referral is important early in the disease course for patients with metastatic disease because their survival is typically 6 months or less.

Deterrence/Prevention:

• Because a calcified (porcelain) gallbladder has up to a 25% incidence of associated gallbladder cancer, this is an indication for a cholecystectomy even in an asymptomatic patient.

• A small percentage (less than 10%) of patients with gallbladder polyps are found to have underlying gallbladder cancer. The risk increases with age and the size of the polyp. A cholecystectomy should be considered if a gallbladder polyp greater than 1 cm in size is found in a patient older than 50 years.

Prognosis:

• Survival at 5 years is correlated with stage of disease at presentation. Only 10-20% of patients present with localized disease. The remainder present with regional or distant spread. According to the SEER registry on gallbladder cancer, the 5-year survival rates for localized, regional, and distant disease are approximately 40%, 15%, and less than 10%, respectively. The median survival for advanced disease is short (2-4 mo).

MISCELLANEOUS

Medical/Legal Pitfalls:

• Although pathologic review of all specimens removed from a patient is standard practice, careful examination of the gallbladder is indicated to rule out carcinoma in high-risk populations (calcified gallbladder, gallbladder polyps).

• If laparoscopic or simple open cholecystectomy has been performed and cancer is discovered after the fact, additional surgery or adjuvant chemoradiation should be considered.