Gallbladder Cancer – Causes, Diagnosis and Treatment
The gallbladder stores bile, which aids in the digestion of fat-containing foods. It is a nonessential organ and can be removed without significant consequences. Gallbladder cancer—also called carcinoma of the gallbladder—is extremely rare. And unless it is very small and found when the gallbladder is removed for other reasons, the treatment now available is not particularly effective.
Because it is so uncommon and because its symptoms mirror those of far more common ailments, cancer of the gallbladder is usually not found until it is at an advanced stage and cannot be surgically removed. In the advanced stages, pain relief and the restoration of normal bile flow from the liver into the intestines are the principal goals of therapy.
Types The majority of gallbladder tumors are found in glandular tissue within the gallbladder (adenocarcinoma). Others originate in the connective tissue (sarcoma) or other tissues (squamous carcinoma). The management for all gallbladder cancer types is the same, always depending upon the extent of the tumor at the time of diagnosis.
How It Spreads Gallbladder cancer tends to spread to nearby tissues and organs such as the liver and intestines. It also spreads through the lymph system to lymph nodes in the region of the liver (porta hepatis). Ultimately, other lymph nodes and organs can become involved.
What Causes It No one factor has been clearly shown to cause gallbladder cancer. Although it occurs most often in people with gallstone disease, it is extremely rare even in such patients. It is not known if bouts of gallstones predispose people to developing this cancer.
At Significantly Higher Risk About 85 percent of people with gallbladder cancer have a history of gallstones (cholelithiasis). Sometimes, although not often, the gallbladder becomes hardened (calcified) from repeated inflammation as gallstones are passed. People with this “porcelain gallbladder” have a higher risk of developing this cancer than do others. The typical patient with gallbladder cancer is an elderly woman with a history of gallbladder problems.
At Slightly Higher Risk Gallstone disease without a “porcelain gallbladder”
No screening tests are available to detect this cancer at an early stage. But, since the gallbladder isn’t essential, people with a calcified gallbladder may consider having it removed as a preventive measure.
Common Signs and Symptoms
There are no clinical signs or symptoms characteristic of gallbladder cancer. Jaundice (the skin turning yellow), bloating, abdominal pain, weight loss, decreasing appetite, fever, nausea, and an enlarging abdominal mass are all signs that may be attributable to gallbladder cancer. Frequently, jaundice is a late development and the other symptoms have been present for a long time. Itching may result from the buildup in the skin of a derivative of bile, bilirubin, which turns the skin yellow. This symptom usually reflects advanced disease.
Physical Examination There are no specific findings for gallbladder cancer on physical examination. Even if the following were found, gallbladder cancer would still not be the prime suspect because it is so uncommon:
•Tender mass below the ribs on the right side of the abdomen.
•Enlarged, hard lymph nodes.
•Jaundice (the skin turning yellow).
•Swelling of the legs (edema).
Blood and Other Tests Diagnostic tests are notoriously inaccurate in their ability to pinpoint gallbladder cancer before surgery. A standard evaluation, however, would include the following:
•A complete blood test, which may be normal or may reveal a decrease in hemoglobin (anemia). The white blood cell count may be normal or increased.
•Liver function tests may be abnormal. The most likely abnormalities are in the serum bilirubin and alkaline phosphatase, indicating a blockage in the bile duct leaving either the liver or the gallbladder.
•Prothrombin time and partial thromboplastin time (PT and PTT) are tests of clotting that may reveal a disorder in patients with poor liver function related to a blocked bile duct.
•An abdominal ultrasound study to view the gallbladder area without exposure to X-rays can confirm that the gallbladder wall has thickened and provide information about the size and characteristics of any mass in the region.
•Swallowing pills with dye that travels to the gallbladder, enabling it to be seen on X-ray (oral cholecystography), or the injection of dye into the bile ducts through the skin followed by an X-ray of the area (percutaneous cholangiography) may be done because of symptoms or an elevated serum bilirubin level. While both studies may document an abnormality within the bile ducts or gallbladder, neither can reliably distinguish between inflammation of the gallbladder (cholecystitis) and gallbladder cancer.
•A CT scan may help determine the extent of the tumor within the gallbladder bed and the possible involvement of other organs.
• Magnetic resonance imaging (MRI) may be helpful in determining if the cancer can be surgically removed, but it is usually not necessary because the CT scan shows similar information.
•If the diagnosis of cancer is confirmed or suspected, a chest X-ray should be obtained. A finding of tumor nodules in the lungs would mean that the disease is already metastatic.
Biopsy If cancer is suspected in a situation not involving gallbladder surgery for other reasons, a biopsy, either with a fine needle (FNA) or regular needle, is always required. This can be done through the skin without significant danger. The tumor cells are characteristic and may enable evaluation of whether surgery should be performed if the other studies suggest that the tumor has spread.
A TNM staging system exists for gallbladder cancer, but for the purposes of deciding on which therapeutic option to use, there are only three stages—localized resectable, localized unresectable, and advanced disease.
Gallbladder cancer can be cured only when it is localized enough to be removed surgically. Unfortunately, virtually the only people with such localized disease are those whose cancer is found unexpectedly when the gallbladder is removed for other reasons.
The goal of the diagnostic work-up is to determine if the cancer can be entirely removed. This is rarely possible because the tumor usually spreads to local regions early in its course. More effective chemotherapy and radiation therapy than are available today are under investigation. These treatments are occasionally useful to relieve symptoms related to the cancer. Although patients with advanced gallbladder cancer have a poor prognosis, measures can be taken to maintain the quality of life.
Surgery Surgery is the only possible cure. If there is no distant tumor spread, the gallbladder as well as the draining lymph nodes and a wedge of normal underlying liver tissue may be removed. This may cure a patient, can help relieve symptoms, and may improve the quality of life.
If a gallbladder cancer is found unexpectedly in the pathology specimen after surgery performed for problems not thought to involve cancer, a second operation may be required. If the tumor is limited to only the superficial layers of the gallbladder, observation may be adequate. If the cancer has spread into the surrounding tissues, lymph nodes, or blood vessels, however, a second operation may be performed to remove those other tissues.
When the tumor cannot fully be removed, it may still be necessary to create a drainage system for the bile from the obstructed gallbladder or bile ducts. This may require surgery, although draining the gallbladder by a tube placed through the skin by a radiologist or through a tube in the stomach and small intestine usually suffices.
The presence of tumor anywhere else in the body—in the lung(s), bone, or lymph nodes, for example—is a clear indication that surgery will not be curative. If the disease has already spread, there is rarely a need to remove a gallbladder cancer, for such surgery involves a difficult recovery period and so may be more damaging to the patient.
Chemotherapy Studies have not yet shown that chemotherapy can prolong the survival of patients with gallbladder cancer. The standard drugs used—5-fluorouracil, capecitabine (Xeloda), and gemcitabine (Gemzar)—may cause tumor shrinkage in 20 to 25 percent of patients. Even with tumor shrinkage, however, patients may be in a worse condition afterward because the tumor usually regrows quickly and the treatments have some side effects.
There is no proven role for adjuvant chemotherapy after a cancerous gallbladder has been removed, but it is logical to consider chemotherapy. In the hope of finding drugs that may work better than the chemotherapy now used, patients should be entered into clinical trials if chemotherapy is planned.
Radiation The usefulness of radiation in gallbladder cancer is limited by the damage it causes to the surrounding noncancerous liver tissue. Radiation may help patients who have small bits of tumor remaining after surgery or those who have had large tumors removed.
Patients who are not candidates for surgery may also benefit from radiation to the gallbladder area, although they are still likely to have recurrent tumors. The toxicity of such radiation may also worsen existing symptoms such as nausea and loss of appetite.
Combined Therapy The combination of external-beam radiation and chemotherapy may play a role after surgery, perhaps prolonging the period before the cancer returns or even curing people who have undergone surgery without complete tumor removal. This treatment is still being studied.
Treatment by Stage
In this stage, the cancer is confined to the superficial layers (mucosa and submucosa) of the gallbladder. Cancers at this limited stage are generally found when the gallbladder is removed because of other problems.
Standard Treatment Experts disagree over the extent of surgery needed for a localized gallbladder cancer. Studies are ongoing, but most experts would recommend
•removal of the gallbladder,
•a lymph node dissection of all the draining lymphatic vessels in the region, and
•the removal of a wedge of about 11⁄2 inches (4 cm) of apparently normal liver.
Such surgery is the most likely treatment to render a patient cancer-free. If the cancer is not recognized until after surgery, the need for a second operation is considered. A patient with a truly limited cancer (superficial) may just be observed closely, but because of the poor prognosis should the cancer recur, it is difficult to argue against the aggressive approach outlined above.
Five-Year Survival About 80 percent. Those with cancers that are still very small but cause symptoms have a somewhat lower five-year survival rate.
•There is no certain role for adjuvant chemotherapy. Although chemotherapy such as 5-fluorouracil (5-FU) or mitomycin-C is often recommended, no studies have shown that the chance of cure can be increased.
•Radiation is often given to the liver area after surgery but has never been proven to be beneficial.
•The use of a combination of 5-FU and radiation therapy following complete removal of the cancer is now being studied.
Despite being a localized mass, the tumor cannot be removed because of the particular way it has spread to local lymph nodes or adjacent liver tissue.
Standard Treatment There is no standard treatment. Patients should be considered for clinical trials aimed at prolonging survival and relieving the symptoms associated with the tumor.
Two-Year Survival Less than 5 percent
Investigational Protocols designed to test the additive benefit of combining radiation with chemotherapy are ongoing.
The cancer has metastasized to distant sites.
Standard Treatment No standard therapy is known to prolong survival in patients with advanced gallbladder cancer. The usual approach is a trial of chemotherapy with a single agent such as 5-FU, capecitabine (Xeloda), or gemcitabine (Gemzar). Even if the tumor shrinks, patients may not benefit because of the side effects of the chemotherapy and because the tumor usually regrows very quickly.
Two-Year Survival Less than 1 percent
Investigational Combination chemotherapy or new drugs may prove to be better in the treatment of advanced gallbladder cancer than therapies now available. Because the side effects are likely to be greater than those caused by single-agent chemotherapy, such treatment should be done in a clinical protocol.
Careful follow-up is important after the removal of a localized gallbladder cancer, although once a recurrent tumor is large enough to be seen on an X-ray, it is probably too large to be cured. Follow-up should include CT scans every two to three months for the first year after surgery, since another small tumor may still be resectable at the time of diagnosis.
•Symptoms associated with jaundice can include severe itching and a general sense of poor health. These symptoms can usually be managed with a drainage procedure to bypass the blockage in the biliary tract. This procedure may include the placing of a tube through the skin or through the stomach. Surgery is rarely necessary to bypass an obstruction. If such drainage is ineffective, itching may be relieved by the use of Benadryl, Atarax, or cholestyramine (Questran). For unexplained reasons, the antibiotic rifampin may also alleviate the itching associated with high bilirubin.
•Pain relief may require large doses of medication. Narcotics must be used carefully, however, since they may have excessive side effects and are metabolized by the liver, which may not be working properly.
•Nonsteroidal anti-inflammatory drugs may be surprisingly effective even against the severe pain associated with gallbladder cancer.
•Water pills (diuretics) to reduce fluid in the abdomen or legs may be helpful but may cause significant imbalance in kidney function if not monitored carefully.
•Nausea can be treated with standard medications, including suppositories.
•Sleep disturbances are common, but sleeping pills should be used carefully, since most are metabolized by the liver.
•Frequent small meals may be necessary, since an abdominal mass may reduce the size of the stomach.
•Patients with severe loss of appetite may be helped by an appetite-stimulating drug called megestrol acetate (Megace).
The Most Important Questions You Can Ask
•Should I see another physician to confirm that this tumor can or cannot be removed for cure?
•Could I benefit from an investigational therapy available at another institution?
•How sick will the proposed chemotherapy make me relative to its potential benefit?
•Can anything be done to improve the quality of my life?