Bile Duct Cancer – Risk factors, Diagnosis, Treatment

Bile duct cancer—also called cholangiocarcinoma—is a rare cancer. Bile is manufactured in the liver and helps the body digest fats. The bile ducts course throughout the liver collecting bile, then travel beyond the liver to connect with the gallbladder and small intestine. Bile duct cancers may, therefore, arise in many locations in and around the liver.

A patient’s prognosis depends largely on where the tumor begins and how large it has grown by the time of diagnosis. The only definitive treatment is the complete surgical removal of the tumor, which is not often possible. If the cancer cannot be entirely removed, the principal goals of therapy become the relief of symptoms caused by the accumulation of bile, and relief from pain.

Types The vast majority of these tumors develop in glandular tissue within the bile duct (adenocarcinoma). Other tissue types include squamous carcinomas and sarcomas. The therapy for all types of bile duct cancer is the same, depending on the extent of the tumor at the time of diagnosis.

How It Spreads Bile duct cancer tends to spread into the adjacent liver, along the bile duct surface, and through the lymph system to lymph nodes in the region of the liver (porta hepatis). Tumors in the bile duct leading from the gallbladder to the common bile duct (cystic duct) can spread to involve the gallbladder. Ultimately, other lymph nodes may become involved, as well as other organs within the abdomen.

What Causes It The cause is unknown. People with chronic inflammatory processes, such as ulcerative colitis and parasitic infections of the bile ducts, are at higher risk for developing this cancer. But no one cause has been clearly demonstrated.

Risk Factors

At Significantly Higher Risk

• People chronically infected with the liver fluke Clonorchis sinensis, which is prevalent in parts of Southeast Asia, may develop bile duct cancer. People may become infected with this parasite by eating raw or pickled freshwater fish from this region. Most people with this infection do not develop cancer.

• People with chronic ulcerative colitis have a higher incidence of both benign inflammatory processes of the bile ducts (sclerosing cholangitis) and bile duct cancer.

• People with congenital abnormalities of the bile ducts (choledochal cysts) are more likely to develop bile duct cancer.

Screening

There are no screening methods to detect bile duct cancer at an early stage.

Common Signs and Symptoms

There are no signs or symptoms unique to bile duct cancer. It usually develops slowly and the symptoms are often very subtle. Jaundice (the skin turning yellow) and itching are the most common signs. Jaundice is caused by the accumulation in the skin of a component of bile (bilirubin) that normally empties into the intestines after traveling through the bile ducts.

Bloating, weight loss, decreased appetite, fever, nausea, or an enlarging abdominal mass are all signs that may be attributable to bile duct cancer. Pain usually signifies advanced disease.

Diagnosis

Physical Examination There are no specific findings on physical examination. Even if the findings associated with bile duct cancer are present, other explanations are far more likely. Findings may include

• jaundice,

• fever,

• a tender mass below the ribs on the right side of the abdomen,

• enlarged, hard lymph nodes, and

• swelling of the legs (edema) and fluid in the abdomen (ascites).

Blood and Other Tests Diagnostic tests are usually done to determine the cause of jaundice. These tests may lead to the diagnosis of bile duct cancer, but a simple gallstone or other illnesses can cause the same problems and are much more likely to be the cause of the jaundice.

• A complete blood count may reveal a decrease in hemoglobin (anemia). A normal white blood cell count makes an infection in the bile duct (cholangitis) less likely, but an increased white count raises the likelihood of infection or cancer.

• Liver function tests may be abnormal, with the likeliest abnormalities being in the serum bilirubin and alkaline phosphatase, reflecting a blockage of flow within the bile duct.

• PT and PTT (prothrombin time and partial thromboplastin time) are tests of clotting that may reveal a disorder in patients with poor liver function caused by an obstructed bile duct.

Imaging

• Abdominal ultrasound images of the gallbladder and bile ducts may reveal an enlargement of the bile ducts behind the blockage, since these channels will enlarge (dilate) when the pressure within the drainage system increases.

• PTC (percutaneous transhepatic cholangiography) involves taking an X-ray after a dye has been injected through the skin into the bile ducts. This can make a “road map” of the bile ducts within and outside the liver and may establish the site of the blockage.

• ERCP (endoscopic retrograde cholangiopancreatography) may be done to investigate the cause of an elevated bilirubin. This technically difficult procedure involves passing an endoscope through the mouth and into the small intestine. The physician operating this scope (endoscopist) identifies the site within the intestines where the bile and pancreatic ducts empty their contents. By injecting dye into this opening and doing an X-ray, a “road map” of the bile ducts may be made. PTC and ERCP may both be necessary to completely define the site and cause of an obstruction and will correctly predict the presence of a cancer about 90 percent of the time.

• MRCP (magnetic resonance cholangiopancreatography) is a newer radiologic technique that, in some centers, may replace ERCP as a means of imaging the bile ducts. MRI (magnetic resonance imaging) may be helpful in determining if the bile duct cancer can be surgically removed.

• CT scanning assesses the extent of the tumor within the bile duct and its extension into the adjacent liver, the lymph nodes, or other structures within the abdomen. Often, bile duct cancer is not seen on a CT scan.

• If the diagnosis of cancer is confirmed or suspected, a chest X-ray should be done to look for tumor nodules in the lungs that would confirm the distant spread of the cancer.

Endoscopy and Biopsy Biopsy, either with a fine needle (FNA) or a regular needle, can be done through the skin without significant danger or through the scope when ERCP is done. The tumor cells may also be found in the bile. They are characteristic, and their presence may help decide whether surgery should be performed if the other studies also suggest the tumor has spread. It can be difficult to obtain an adequate biopsy sample because the tumors are often small and lie within normal liver tissue.

Staging

A TNM staging system is used for bile duct cancer, but when deciding which treatment option to use, there are really only two stages—localized and unresectable disease.

Treatment Overview

The optimal treatment for bile duct cancer is surgery. Unfortunately, by the time symptoms develop, the cancer has usually spread throughout the bile ducts and into the liver, meaning that the tumor cannot be entirely removed.

Chemotherapy and radiation therapy are occasionally useful to relieve symptoms. Although they have not been shown to be effective in curing the cancer, these measures can be taken to maintain the quality of life.

Surgery The decision to take a surgical approach depends on the overall health of the patient and on the location of the tumor. If a patient is ill from complications of the cancer—jaundice or infection, for example—a drainage tube (stent) should be placed in the bile ducts to treat the complications. The patient then has to be allowed to recover before an operation is attempted.

If the tumor is in either the left or the right bile duct and has not spread to the lymph nodes, it may be possible to remove the tumor with its accompanying lobe of the liver because people with normal liver function do not need both lobes.

Tumors involving the junction of the right and left bile ducts (Klatskin tumor) create more problems. The tumor may not have spread, but its removal requires rebuilding the bile ducts. This can be done by removing the entire tumor and attaching a loop of intestine to the liver where the cut ends of the bile ducts are draining (called a Roux-en-Y). This is a difficult operation and the overall health of the patient is an important factor in deciding whether to perform it.

Bile duct cancers can also occur at the far end of the duct, near where it empties into the intestine. Removing these tumors may also require a Roux-en-Y, as well as removal of parts of the intestines and pancreas (called a Whipple procedure). This extensive surgery is extremely complicated and has many side effects. It should be done only when a tumor has not spread beyond the local area.

Chemotherapy Studies have not shown that chemotherapy can prolong survival, but the standard drugs used (gemcitabine [Gemzar], capecitabine [Xeloda], and 5-fluorouracil) may cause tumors to shrink and help 20 to 25 percent of patients. Even with tumor shrinkage, however, patients may not be better off after chemotherapy. The treatment has side effects and the tumor ultimately regrows.

There may be a role for chemotherapy after surgery, although this has not been studied systematically. In the hope of finding a better chemotherapy treatment and improving survival, patients should be considered for clinical trials if chemotherapy is planned.

Radiation Radiation is effective against bile duct cancers and may play a significant role. If the tumor is fairly small, it may be treated with radiation without causing much damage to the surrounding noncancerous liver tissue. A newer computer-directed radiation technique called conformal radiation may allow for the radiation beam to pinpoint the tumor and spare the surrounding uninvolved liver, although it is often difficult to define the actual extent of bile duct tumors.

Treatment may include placing a radiation-containing probe in the bile duct (brachytherapy). This therapy may also apply to patients with a small bit of tumor left after surgery or as a supplemental (adjuvant) therapy when the surgery is thought to have been complete but there is a suspicion that microscopic deposits of tumor are still present. Studies evaluating the role of radiation therapy are ongoing.

Combined Therapy The combination of radiation and chemotherapy may play a role as adjuvant therapy. This treatment, which should be done as part of a clinical trial, may delay any recurrence of the cancer or even cure people who have already had surgery.

Treatment by Stage

 Localized

At this stage, the cancer is confined to the bile duct. It is quite rare to find a bile duct cancer at this limited stage, for it would be unlikely to cause an obstruction of the bile flow when it is very small.

Standard Treatment Surgery can be done with hopes of a cure. The extent of surgery necessary depends on the tumor’s location and size. It may be possible to remove a tumor limited to a small portion of either the right or the left bile duct with its surrounding liver in a routine operation. But cancers involving the bile ducts at their junction within the liver require removal of liver tissue and then the complicated reconstruction of the bile drainage system. Tumors close to the intestine and pancreas may demand even more difficult surgery.

Whatever the extent of the surgery, tubes may have to be left within the bile duct system for a time to ensure against bile leakage or the formation of scar tissue within the bile ducts.

It is not known whether drainage tubes should be placed through the bile duct blockage before surgery. If patients are ill because of the obstruction—the bile has become infected, for example—then a stent should be inserted to enable the patient to be in better condition for the surgery. Radiation to the tumor site is an alternative if patients are too sick to have surgery.

Unfortunately, even with meticulous surgery and careful screening, the majority of tumors will regrow within the bile ducts, in the nearby liver tissue, or elsewhere in the body. So it is generally agreed that treating the surgical area with radiation after the tumor has been removed is useful in that it may help to destroy any remaining tumor cells.

The chemotherapy drug 5-fluorouracil or capecitabine is often given at the same time as the radiation in an effort to improve the effectiveness of treatment. This combination therapy is felt to be better than other treatments.

Five-Year Survival Up to 25 percent

Investigational Various combinations of surgery, radiation, and chemotherapy may be considered. The most extreme approach involves pretreating localized tumors with chemotherapy and radiation, then performing a liver transplant. There is some evidence that this aggressive approach can eradicate the cancer in highly selected patients.

 Unresectable

The tumor cannot be removed because it has spread to local lymph nodes, liver tissue, or elsewhere in the body.

Standard Treatment There is no standard treatment, so chemotherapy and/or radiation therapy clinical trials should be considered.

Significant relief of symptoms may be achieved. Patients with symptoms such as itching or infection may benefit from a procedure to create a bypass system for the bile. Such a bypass tube (stem) can be placed through the skin during percutaneous transhepatic cholangiography or through a scope during ERCP.

With the ERCP stent placement, the tube may drain into the intestines and a collecting bag may not be needed. Occasionally, neither of these methods drains the bile successfully. In that case, surgery designed to create a bypass channel may be done.

Two-Year Survival Less than 1 percent

Investigational

• Clinical protocols designed to test the additive benefit of radiation and chemotherapy are ongoing.

• Patients who wish to try chemotherapy may be offered new drugs.

Treatment Follow-Up

Careful follow-up is important after the surgical removal of a localized cancer because once a recurrent tumor is large enough to be seen on X-ray, it is probably too large to be cured.

CT scans should be done every two to three months for the first year after curative surgery, since an early recurrence may still be removed if it is small enough at the time of diagnosis.

Supportive Therapy

• Problems associated with jaundice can include severe itching and infections in the bile. If the drainage procedures described above are not effective, itching will often be relieved by Benadryl, Atarax, or cholestyramine (Questian). For unexplained reasons, the antibiotic rifampin may also alleviate the itching associated with jaundice.

• Large doses of narcotics may be needed to relieve pain. Such drugs may have excessive side effects, since they are eliminated by the liver, which may not be functioning properly.

• Nonsteroidal anti-inflammatory drugs may be surprisingly effective even against the pain associated with bile duct cancer.

• Frequent small meals may be necessary to get enough nutrition, since an abdominal mass may reduce the size of the stomach.

• Water pills (diuretics) can reduce fluid in the abdomen or legs. They may cause significant imbalance in kidney function, however, and can create problems if not carefully monitored and adjusted.

• Nausea will often be relieved by standard medications, including suppositories.

• Loss of appetite may be helped by megestial (Megace).

• Sleep disturbances are common, but most sleeping pills are broken down by the liver, so they should be used carefully.

The Most Important Questions You Can Ask

• Should I see another physician to confirm that this tumor can or cannot be removed?

• Can the drainage of the bile ducts be done through the intestines so I won’t have to have a tube coming out through my skin?

• Am I a candidate for an investigational therapy at another medical center?

• How sick will radiation and/or chemotherapy make me, and does the potential benefit make it worthwhile?

• Can anything be done to improve the quality of my life?

• Is the treatment worthwhile if the tumor is too advanced for surgery?