Gallbladder cancer

ALSO KNOWN AS: Gallbladder carcinoma

RELATED CONDITIONS: Bile duct cancer (cholangiocarcinoma)

DEFINITION: Gallbladder cancer is a rare cancer that starts in the lining of the gallbladder. The gallbladder stores bile, a liquid necessary for the breakdown of fat. Most gallbladder cancers are adenocarcinoma. Other types of gallbladder cancer include squamous cell carcinoma and small-cell carcinoma.

Risk factors: Gallbladder cancer occurs at a 66 percent higher rate in women than in men and usually in people older than age seventy. American Indians and Hispanics are at the highest risk for the disease. Worldwide, a high incidence of disease occurs in Chile, Bolivia, and parts of Asia. Obesity and a sedentary lifestyle have been identified as risk factors for gallbladder cancer.

At least three out of four gallbladder cancer patients have gallstones, but less than 1 percent of patients with gallstones will go on to develop gallbladder cancer. Cysts in the bile ducts also raise the risk of gallbladder cancer. Calcification (hardening) in parts of the gallbladder increases the risk of gallbladder cancer. People with calcifications throughout the gallbladder wall have no higher risk than the general population.

Etiology and the disease process: There is strong circumstantial evidence that gallbladder cancer results from constant inflammation of the gallbladder. Gallstone disease causes repeated irritation and inflammation of the gallbladder. Most patients with gallbladder cancer have gallstones in addition to their cancer. Patients with large gallstones (greater than three centimeters) are at a greater risk of developing gallbladder cancer. Also supporting the inflammation theory is that repeated infections in the gallbladder increase a person’s risk of this cancer.

Gallbladder cancer spreads through the lymph nodes and vessels and blood vessels. Lymph vessels, which extend into every organ in the body, collect abnormal or foreign cells into the lymph nodes. This is why gallbladder cancer surgery often includes the removal of the lymph nodes in the area of the gallbladder, liver, and pancreas.

Another route through which the cancer spreads is directly into the liver. Because there is no separation between the gallbladder and liver tissues, a gallbladder tumor can directly enter the liver.

Incidence: The disease is rare, with just over 12,000 adults diagnosed with gallbladder and other biliary cancers each year. Of these, four in ten are gallbladder cancers. The incidence of the disease decreased by 50 percent between 1973 and 2007.

Symptoms: Symptoms of gallbladder cancer do not appear until the disease is advanced. When they appear, they are not specific and often identical to symptoms of other (benign) gallbladder or liver problems. Symptoms of gallbladder cancer may include:

• Enlarged liver
• Fever
• Jaundice (yellowing of the skin and whites of the eyes)
• Loss of appetite
• Nausea or vomiting
• Pain in the upper right part of the abdomen
• Severe itching
• Swelling of the stomach due to fluid accumulation (ascites)
• Weight loss

Screening and diagnosis: There is no test to screen for gallbladder cancer. Because the symptoms are often the same as for other liver or biliary diseases, unless doctors find cancer during surgery to remove gallstones, diagnosis is usually delayed until the cancer is advanced and symptoms appear.

Tests for suspected gallbladder cancer include:

• A complete physical examination
• Liver function tests
• Cancer antigen (CA) 19-9 assay (while this test identifies a marker that is not specific for gallbladder cancer, it may focus suspicion in combination with other test results)
• Endoscopic retrograde cholangiopancreatography (ERCP) is an X-ray of the bile ducts that uses a lighted tube (endoscope) passed from the mouth to the small intestine. A smaller tube inside the endoscope delivers a special dye into the bile ducts, and X-rays of the dye can help diagnose blockage or narrowing of the ducts.
• Blood tests which may show abnormal amounts of certain chemicals in the blood
• Percutaneous transhepatic cholangiography (PTHC) is an X-ray of the liver and bile ducts during which a special dye is injected into the liver. X-rays follow the dye through the bile ducts. PTHC helps diagnose blockage or narrowing of the bile ducts.
• Biopsy, the examination of a tissue sample under a microscope
• Computed tomography (CT) scan and magnetic resonance imaging (MRI), usually the best diagnostic tools to verify gallbladder cancer

Staging of gallbladder cancer is done according to the criteria of the American Joint Commission on Cancer (AJCC). These criteria use the TNM (tumor/lymph nodes/metastasis) staging system, which looks at the tumor location, whether the cancer has invaded any near or distant lymph nodes, and whether the cancer has spread (metastasized) to other parts of the body. The TNM system for gallbladder cancer is:

• TX: Primary tumor cannot be evaluated.
• T0: No evidence of primary tumor is found.
• Tis: The cancer is limited to the innermost layer of the gallbladder (mucosa).
• T1a: The tumor invades the lamina propria (the layer next to the mucosa).
• T1b: The tumor invades the muscle layer (the next layer).
• T2a: The tumor invades the layer surrounding the muscle on the peritoneal side
• T2b: The tumor invades the layer surrounding the muscle on the hepatic side
• T3: The tumor goes through the serosa or into the liver or one other organ, such as the stomach, small intestine, or pancreas.
• T4: The tumor invades the main portal vein (connecting the digestive tract to the liver) or hepatic artery, or invades multiple organs outside the liver.
• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node spread is found.
• N1: Metastases to one to three regional lymph nodes.
• N2: Metastases to four or more regional lymph nodes
• M0: No distant metastasis is found.
• M1: Distant metastasis is found.

Staging is as follows:

• Stage 0: Tis, N0, M0
• Stage I: T1, N0, M0
• Stage IIA: T2a, N0, M0
• Stage IIB: T2b, N0, M0
• Stage IIIA: T3, N0, M0
• Stage IIIB: T1-3, N1, M0
• Stage IVA: T4, N0-1, M0
• Stage IVB: Any T, N2, M0 or Any T, Any N, M1

Treatment and therapy: The only realistic treatment option is surgery. Removal of the gallbladder can cure patients with Stage 0 or I cancer.

There are several types of gallbladder removal surgery (cholecystectomy):

• Simple cholecystectomy: Removal of the gallbladder alone
• Extended cholecystectomy: Removal of the gallbladder, a small area of the liver right next to the gallbladder, and area lymph nodes
• Radical cholecystectomy: Removal of the gallbladder, a wedge-shaped part of the liver, the common bile duct, tissues between the liver and the small intestine, and the lymph nodes along the path between the liver and the small intestine

The type of surgery a patient will have depends on how advanced the cancer is. Only one in five gallbladder cancers are found in the early stages. When surgery is not a treatment option, palliative surgery may help relieve symptoms. Palliative surgery does not treat or control the disease. When surgery is no longer an option, patients should consider enrolling in clinical trials of emerging treatments.

Follow-up radiation after surgery helps prolong survival in some patients. Chemotherapy may be added to surgery and radiation. Chemotherapy drugs commonly used to treat gallbladder cancer are Gemcitabine (Gemzar), Cisplatin (Platinol), 5-fluorouracil (5-FU), Capecitabine (Xeloda), and Oxaliplatin (Eloxatin). Radiation and chemotherapy (alone or in combination) can also be used before surgery to try to shrink a large tumor.

Prognosis, prevention, and outcomes: The prognosis is usually poor because diagnosis usually occurs at an advanced stage. The prognosis depends on the stage of the cancer at diagnosis. When diagnosed early (usually during surgery to remove gallstones), many patients become cancer-free. The five-year survival rate for individuals with localized tumors is 69 percent. Those with regional tumors have a five-year survival rate of 28 percent, and those with cancer that spreads to distant organs have a five-year survival rate of 3 percent.

Lifestyle modifications like weight loss and exercise help prevent gallbladder cancer.

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