Cancer of the gallbladder is a malignant tumor arising from the gallbladder. Carcinoma of the bile duct is a malignant tumor of the bile ducts that may occur within or outside the liver. Carcinoma of the gallbladder occurs more frequently compared to the bile duct cancer. Survival rate is poor since most patients are diagnosed at a late stage in the disease. Incidentally discovered gallbladder cancers during routine cholecystectomy for stones may carry better prognosis, if the disease is early. Both these tumours are generally locally aggressive and spread to distant sites only in late stages.
Pathophysiology of the Diseases:
The gallbladder and bile ducts together form the biliary tract. Bile is manufactured by the liver to aid in the digestion of food. Bile ducts are tubular structures, similar to blood vessels, which carry the bile from the liver to the small intestine. Like the tributaries of a river, the small bile ducts in the liver converge into two large bile ducts. These join to form a large bile duct outside the liver. The gallbladder is a hollow oblong organ that is stuck to the undersurface of the liver and connects to the bile duct. Bile flows into the gallbladder, where it is concentrated by the absorption of water. During times of food digestion, the gallbladder contracts to eject the concentrated bile into the large bile duct. Which drains the bile by gravity into the small intestine, where the bile helps to digest food. Carcinoma of the gallbladder typically arises from the columnar (column-shaped) cells lining the inner surface of the gallbladder. The tumor grows and penetrates through the wall of the gallbladder, invading adjacent portions of the liver or spreading to other organs in the abdominal cavity. Caner cells also spread through lymphatic channels that lies on the surface of the gall bladder and the bile ducts to reach lymph nodes.
Similarly, carcinoma of the bile duct usually originates from columnar cells along the inner surface of the bile ducts. A tumor may arise anywhere in the system of bile ducts, either within (intrahepatic) or outside of (extrahepatic) the liver. Bile duct tumors spread by local invasion of neighboring structures or by way of lymphatic vessels. Although these tumors are slow growing, they can block the flow of bile through the bile ducts. This blockage results in jaundice and occasionally can get infected.
Approximately 5000 cases of carcinoma of the gallbladder are diagnosed in the United States each year. Among all the countries in the world, Israel has the highest yearly incidence, with 7.5 cases per 100,000 men and 13.8 cases per 100,000 women. Northern India, Mexico, Bolivia, Chile, and northern Japan and also have a high incidence. The cancer is less common in Nigeria and Singapore.
Carcinoma of the bile duct is less common than carcinoma of the gallbladder. About 2500 cases are diagnosed yearly in the U.S. with an incidence of approximately one case per 100,000 people per year. The cancer afflicts Native Americans more often, however, with about 6.5 cases per 100,000 per year. Worldwide, the incidence is highest in Japan and Israel.
Almost 3 times as many women are affected with carcinoma of the gallbladder than men. Carcinoma of the bile duct occurs in men slightly more often than in women. Both cancers are usually detected when the patient is in the early-to-middle sixties.
No underlying cause has been identified for carcinoma of the gallbladder or bile duct. However, several associations have been observed. Risk factors associated with carcinoma of the gallbladder:
Several anatomic abnormalities, including gallbladder polyps, anomalous connections between the biliary tract and the intestine, and congential biliary dilatation.
Risk factors associated with carcinoma of the bile duct:
Other chemical exposures, especially among workers in the aircraft, rubber, and wood finishing industries.
Since there are no specific symptoms of carcinoma of the gallbladder, the cancer is usually diagnosed when it has already progressed to an advanced state. Patients may complain of abdominal pain or distention, weight loss, nausea, or anorexia. Jaundice is the first symptom in some patients and is a bad prognostic sign. This occurs when the tumor directly or indirectly causes an obstruction in the normal flow of bile from the liver to the small intestine. Bilirubin, a component of bile, builds up within the liver and is absorbed into the bloodstream in excess amounts. This can be detected in a blood test, but it can also manifest as yellowish discoloring of the skin and eyes. The patient may also experience generalized itching, due to the deposition of bile components in the skin. Occasionally an abdominal mass in the upper right or central region of the abdomen can be felt on physical examination.
Jaundice is the most common symptom of carcinoma of the bile duct, resulting from blockage of the bile duct with tumor. The excess bile components in the bloodstream can cause pruritis and dark coloration of the urine. Normally, a portion of the bile is excreted in stool; bile actually gives stool its brown color. But when the biliary tract is obstructed by tumor, the stools may appear pale. Abdominal pain, fatigue, weight loss, and anorexia are less common symptoms. Occasionally, if obstruction of the biliary tract causes the gallbladder to swell enormously, the gallbladder may be felt during a physical examination. Sometimes the biliary tract can become infected, but this is normally a rare consequence of invasive tests (such as ERCP). Infection causes fever, chills, and pain in the right upper portion of the abdomen.
Carcinoma of the gallbladder and bile duct are staged according to the tumor-node-metastasis (TNM) system of the American Joint Commission on Cancer (AJCC). This staging scheme assesses the invasiveness of the tumor, the involvement of nearby lymph nodes, and the extent of distant spread. A higher stage signifies worse prognosis.
Stage I tumors of the gallbladder are confined to the inner layers of the bile duct itself. Stage II tumors extend to the outer layers. Stage III tumors have spread to nearby lymph nodes or a directly adjacent organ. Stage IV tumors have invaded deeply into the liver or have spread to multiple adjacent organs. Involvement of distant organs or lymph nodes is also included in Stage IV.
The staging of carcinoma of the bile duct is similar to that of the gallbladder. Stage I tumors are confined to the inner layers of the bile duct itself. Stage II tumors extend to the outer layers. Stage III tumors have spread to nearby lymph nodes. Stage IV tumors have invaded other organs in the abdomen or distant lymph nodes .
Laboratory tests of the blood may aid in the diagnosis of both cancers. The most important one is the test for elevated bilirubin levels in the bloodstream. Elevated levels of other enzymes may also point to obstruction of the biliary tract. Carcinoma of the bile duct produces certain compounds that can be detected in the bloodstream. These tumor markers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are especially useful in diagnosing carcinoma of the bile duct associated with primary sclerosing cholangitis.
When symptoms, physical signs, and blood tests are concerning for an abnormality of the biliary tract, the next step involves imaging tests. The tests useful for carcinoma of the gallbladder and bile duct are similar. The objective is to determine the size and location of the tumor, as well as the extent of spread to nearby structures. Noninvasive tests can supply much anatomic information in rapid fashion. Both ultrasound and computed tomography (CT) can detect the actual tumor and the extent to which it has spread. Dilatation of the gallbladder or bile ducts can be seen. CT adds the ability to detect enlarged lymph nodes throughout the abdominal cavity. Magnetic resonance imaging (MRI) has also been used to determine the involvement of bile ducts and blood vessels.
If these tests indicate the presence of a tumor, then cholangiography usually follows. This procedure involves injecting dye into the biliary tract to obtain anatomic images of the bile ducts and the tumor. The biliary tract is accessed directly through the skin or endoscopically (through the intestine via the mouth.) The specialist that performs this test can obtain samples of cells from the tumor to allow diagnosis under the microscope. Small tubes, or stents, can be placed into a partially obstructed portion of the bile duct to prevent further obstruction by growth of the tumor. This is vitally important since it may be the only intervention that is possible in certain patients. Cholangiography is an invasive test that carries a small risk of infection of the biliary tract which may preclude any radical surgery that may be required.
Angiography can determine if the tumor has spread to blood vessels. This is especially crucial in planning surgical resection of the tumor. If certain blood vessels are encased with tumor, surgical resection may not be possible.
If samples of cells are not obtained by cholangiography, they can be aspirated directly from the tumor under guidance of ultrasound or CT (FNAC). The treatment of bile duct tumour is usually not affected by the specific type of cancer cells that comprise the tumor. For this reason, some physicians forego biopsy.
For both carcinoma of the gallbladder and bile duct, the only hope for cure lies with surgical resection of the tumor and all involved structures. Unfortunately, the cancer has usually spread too far when the diagnosis is made. Seventy-five percent of patients with carcinoma of the gallbladder and 90% of those with carcinoma of the bile duct are diagnosed too late for surgical cure.
Thus, in the treatment of these cancers, the first question to answer is if the tumor may be safely resected with reasonable benefit to the patient. Resection may be impossible if the cancer involves certain blood vessels or has spread widely. Sometimes further invasive testing with laparoscopy is required. Laparoscopy is a surgical procedure that allows the surgeon to directly assess the tumor and nearby lymph nodes without making a large incision in the abdomen. If the tumor is resectable, and the patient is healthy enough to tolerate the operation, the specific type of surgery performed depends on the location of the tumor.
Residual cancer may remain even if curative resection of gallbladder cancer is attempted. There is some evidence that radiation may improve survival in these patients. However, this evidence is derived from small trials. The use of radiation in the treatment of gallbladder cancer requires further investigation. Chemotherapy has not been proven to be very effective. When utilized, it is usually given in combination with radiation.
Radiation can be applied in several modes for the treatment of carcinoma of the bile duct. Radiation before surgery can shrink the size of the bile duct tumor in order to aid resection. Radiation after surgical resection has improved survival in some trials. Brachytherapy is a technique in which small seeds of radioactive agents are placed in the tumor during surgery, allowing concentrated doses of radiation to be delivered to the tumor while sparing nearby tissue. This technique is sometimes combined with postoperative radiation. In some patients who cannot undergo surgery, radiation alone may also lengthen survival. As in carcinoma of the gallbladder, chemotherapy is usually given in combination with radiation.
When long-term survival is not likely due to advanced carcinoma of the gallbladder or bile duct, the focus of therapy shifts to improving quality of life. Jaundice and blockage of the stomach are two problems faced by patients with extensive disease. These can be treated with surgery, or alternatively, by special interventional techniques employed by the gastroenterologist or radiologist. A stent can be placed across partially obstructed bile ducts in order to re-establish the flow of bile and relieve jaundice. A small feeding tube can be placed in the small intestine to allow feeding when the stomach is blocked.
The prognosis of a patient with either of these tumors depends on the stage and resectability of the tumor.
Stage I carcinoma of the gallbladder is associated with an excellent prognosis. Survival rate declines with advancing stage - 25% for stage II, 12% for stage III, and 1-2% for stage IV tumors. Since most patients are diagnosed with late-stage disease, less than 5% of all patients live longer than 5 years after diagnosis.
Carcinoma of the bile duct is also associated with poor survival. The worst prognosis is for patients who can only tolerate placement of a stent within the tumor, without undergoing surgical resection, radiation, or chemotherapy. Patients who undergo radiation and chemotherapy without surgical resection may survive up to 7 to 17 months. Surgical resection plus radiation and chemotherapy is associated with about a 17 to 28 month survival.