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Overview +
Approximately 9,500 new patients are diagnosed with cancer of the biliary tract (the gallbladder and bile ducts) each year in the United States. This is the second most common type of cancer to involve the region of the liver, following cancer of the hepatocytes (hepatocellular carcinoma). Each year in the USA, 3600 patients will die of biliary tract cancer, accounting for approximately 1% of all deaths from cancer. Biliary tract cancers are notoriously challenging to diagnose and treat.
The Johns Hopkins Medical Institutions is a leader in the treatment and investigative study of biliary tract cancer. We have created this Web site to give patients and physicians access to the latest clinical and research developments related to this disease, as well as to the multidisciplinary team assembled here to fight biliary tract cancer.
Symptoms +
Patients with bile duct cancer most often become symptomatic when the cancer obstructs (blocks) the drainage of bile. Because bile cannot be excreted into the bowel, the bilirubin pigments accumulate in the blood, causing jaundice (yellowing of the skin and the whites of the eyes) in 90% of patients. The jaundice is usually associated with itching of the skin (also called "pruritus"). The body compensates partially and excretes some of this bilirubin via the urine, so patients may have dark (cola colored) urine. Because bile cannot reach the intestine, the patient's stools become white (clay colored).
Other symptoms result from inflammation secondary to tumor obstruction. Patients with gallbladder cancer may have pain in the right upper portion of the abdomen. This pain is a result of inflammation of the gallbladder (cholecystitis) due to blockage of the cystic duct. In fact, approximately 1% of patients who undergo cholecystectomy (surgical removal of the gallbladder) for suspected cholecystitis prove to have unsuspected gallbladder carcinoma. Distal bile duct tumors near the ampulla of Vater, the point at which the bile drains into the bowel, obstruct the pancreatic duct and lead to inflammation of the pancreas (pancreatitis).
Anatomy & Physiology +
The anatomy of the biliary tree is a little complicated, but it is important to understand. The liver's cells (hepatocytes) excrete bile into canaliculi, which are intercellular spaces between the liver cells. These drain into the right and left hepatic ducts, after which bile travels via the common hepatic and cystic ducts to the gallbladder. The gallbladder, which has a capacity of 50 milliliters (about 5 tablespoons), concentrates the bile 10 fold by removing water and stores it until a person eats. At this time, bile is discharged from the gallbladder via the cystic duct into the common bile duct and then into the duodenum (the first part of the small intestine), where it begins to dissolve the fat in ingested food.
The liver excretes approximately 500 to 1000 milliliters (50 to 100 tablespoons) of bile each day. Most (95%) of the bile that has entered the intestines is resorbed in the last part of the small intestine (known as the terminal ileum), and returned to the liver for reuse.
The many functions of bile are best understood by knowing the composition of bile:
Bile Salts (cholates, chenodeoxycholate, deoxycholate): these are produced by the liver's breakdown of cholesterol. They function in bile as detergents that dissolve dietary fat and allow it to be absorbed. Hence, disruption of bile excretion disrupts the normal absorption of fat, a process called malabsorption. Patients develop diarrhea because the fat is not absorbed (steatorrhea) , and develop deficiencies of the fat-soluble vitamins (A, D, E, and K).
Cholesterol and phospholipids-while only 4% of bile is cholesterol, the secretion of cholesterol and its metabolites (bile salts) into bile is the body's major route of elimination of cholesterol. Phospholipids, which are components of cell membranes, enhance the cholesterol solubilizing properties of bile salts. Inefficient excretion of cholesterol can cause an increased serum cholesterol. This predisposes to vascular disease (heart attacks, strokes, etc.)
Bilirubin-while this comprises only 0.3% of bile, it is responsible for bile's yellow color. Bilirubin is a product of the body's metabolism of hemoglobin, the carrier of oxygen in red blood cells. Disruption of the excretion of this component of bile leads to a yellow discoloration of the eyes and skin (jaundice).
Protein and miscellaneous components
Bile production and recirculation is the main excretory function of the liver. Tumors that obstruct the flow of bile from the liver can also impair other liver functions. Therefore, it is necessary to understand these other functions to understand the symptoms that these tumors can cause. These include:
Metabolic functions, such as the maintenance of glucose (blood sugar) levels
Synthetic functions, such as the synthesis of serum proteins such as albumin, blood clotting (coagulation) factors, and complement (a mediator of inflammatory responses)
Storage functions, such as the storage of sugar (glycogen), fat (triglycerides), iron, copper, and fat soluble vitamins (A, D, E, and K)
Catabolic functions, such as the detoxification of drugs
Diagnosis +
Many types of tests are used to help diagnose bile duct cancer. These can be grouped as radiology, serology, and pathology.
An improvement on the standard (transabdominal) ultrasound.
Ultrasonography of the liver and gallbladder is usually the first radiologic study used to evaluate jaundice or right-upper quadrant (abdominal) pain. During standard ultrasound the probe is placed externally on the abdomen which limits the resolution of the images. Ultrasound often detects large gallbladder cancers, but often misses smaller extrahepatic bile duct cancer. Standard CT images are often not optimal for diagnosing subtle abnormalities in the bile ducts and other organs. EUS is an improvement of this technique.
Procedure: For an EUS, the ultrasound probe is placed in close proximity to the bile ducts by attaching it to the end of a standard gastrointestinal endoscope and passing the scope in the mouth, down the esophagus and into the stomach and duodenum . This produces a much clearer image than a transabdominal ultrasound.
Accuracy:
- EUS enables the investigator to identify abnormalities 1 cm or larger. There are small bile duct cancers that can be detected with EUS that cannot be visualized currently with a CT scan. Technological improvements are enabling a generation of more accurate images of the bile ducts and such improvements are expected to continue.
- It is the most accurate method for detecting the spread of cancer to the portal vein (not as accurate for arterial involvement).
- EUS will visualize masses of less than 1 cm but often will not be able to determine whether the mass is a cancerous. Fine needle aspiration done in conjunction with EUS may overcome this limitation.
- The main variable in the success of an EUS investigation is the experience of the endoscopist. The technique is difficult and the optimal use of this technique depends on the considerable skill of the endoscopist. Many centers now have endoscopists trained in the technique, but EUS is still not available at all medical centers.
Risks: When done in conjunction with FNA there is a low risk of complication, 5 out of 124 patients 1.1%), all non-fatal complications. Fever, inflammation, perforation of duodenal or esophageal wall, hemorrhage of cystic tumor.
Magnetic Resonance Imaging is becoming more sensitive than CT scanning, is less invasive and is slowly becoming more popular. CT and MRI have the added benefit of detecting enlarged lymph nodes near the tumors, which can suggest that a cancer has spread (metastasized) to the lymph nodes.
Cholangiography, which involves the injection of a radioopaque dye into the biliary system, is the procedure of choice for determining the extent of tumor in the biliary tract. The procedure is done either through the skin (Percutaneous Transhepatic Cholangiography-PTC) or through an endoscope fed through the esophagus and into the duodenum.
During this procedure an X-ray is taken of the pancreatic duct and bile ducts. These ducts drain secretions from the pancreas and liver respectively. Obtaining such pictures requires that an endoscope be placed in the mouth through the esophagus and stomach, then into the duodenum.
Procedure:
The patient is sedated and given potent pain relievers (opiate) after on overnight fast. A local anesthetic is sprayed to the back of the throat. Frequently, muscle relaxants are used to relax the duodenum and ampulla (an anticholinergic drug, or glucagon, nitroglycerin). During the test patients are monitored to ensure that they are not oversedated. The monitoring includes a pulse oximeter (a probe fastened to the patient's finger that measures blood oxygen concentration) and a heart rate monitor. During the ERCP, the degree of sedation is much greater than that used for an EGD, so often the patient is asleep.
Using a modified endoscope, the investigator visualizes the duodenum on a monitor and finds the small opening where the bile duct and pancreatic duct empty into the duodenum (the ampulla of Vater). A thin catheter is passed through an opening in the endoscope and through the ampulla. Once the catheter has been placed through the opening (cannulated), a dye is injected into the pancreatic and bile ducts. This enables images of these ducts to be obtained. X-rays are taken of the abdomen over the area of the bile ducts and gallbladder and are examined on screen by the attending physicians.
Despite the medication, occasionally the patient may feel discomfort and may retch. If discomfort occurs additional pain relief is usually provided. Symptoms arising from complications may also rarely occur.
Accuracy:
Will show the indirect effects of bile duct cancer such as blockage or dilatation of the ducts and inflammation of the tissue. Similar symptoms can be caused by conditions such as chronic pancreatitis, sclerosing cholangitis, or stones in the pancreatic or bile ducts. By examining the pattern of these changes, it is possible to predict with a high degree of certainty if an abnormality is a cancer.
An ERCP can detect an abnormality suspicious of cancer in about 9 out of 10 patients who are investigated for possible adenocarcinoma. Patients who have very small cancers, less than 2 cm, that currently do not alter the main ducts of the pancreas or the bile duct will not be visible.
Occasionally, it can be very difficult to tell if an abnormality in the bile duct is due to cancer or inflammation. Tissue biopsy provides confirmation of the presence of cancer
Results:
If the test results are abnormal, a sample of biliary fluid from the bile duct or a sample of tissue by biopsy can be obtained if necessary. This can be done either during the ERCP by positioning a biopsy forceps while looking at it on screen. Alternatively, the fluid or tissue sample can be obtained by visualizing the are of concern using other imaging techniques and performing a needle biopsy (FNA).
As a Treatment:
Most importantly, if a bile duct cancer is present and the patient is not a candidate for curative surgery, therapeutic procedures can be performed using ERCP. These procedures can provide considerable relief for the patient with minimal inconvenience or risk. Bile duct cancers frequently block the bile duct that prevents the proper flow of bile from the liver. The therapeutic intervention typically alleviates symptoms caused by duct blockage such as jaundice, generalized and progressive itching, liver damage, inadequate digestion of food, a risk of bacterial infection of the blood and severe pain. Placing a stent into the bile duct to allow bile drainage can extend an individual's life and improve their quality of life. The patient does not feel the presence of the stent in their bile duct or pancreatic duct.
Risks:
The main complications of the ERCP as a diagnostic procedure are pancreatitis, infection and bleeding.
The insertion of a therapeutic stent can have complications such as bleeding, inflammation of the pancreas (pancreatitis), bile duct damage and leakage, and infection. Bleeding and pancreatitis is more likely if a large (wide-bore) stent is placed as it requires a cut to be made to enlarge the opening of the narrow ampulla where the bile and pancreatic fluid enters the duodenum (see figure). The cut primarily targets a small sphincter muscle surrounding the ampulla (hence, the procedure is termed a sphincterotomy).
Overall, less than 1 in 10 individuals will have such a complication and severe life-threatening complications are rarer (1-2%). The risk of a complication when a sphincterotomy is not performed is less (2-5%) and depends on the number and size of the stents inserted. Usually therapeutic ERCP can be done as a same day procedure without the need for an overnight hospital stay. If complications occur or are suspected hospitalization might be required. Biliary stents usually succumb to blockage after several months as a result of further cancer growth. This may require periodic stent replacement.
There is also a small risk of an allergic reaction to the dye, which contains iodine. Rarely, drugs used to relax the ampulla of Vater can have side effects such as nausea, dry mouth, flushing, urinary retention, rapid heart rate (sinus or supraventricular tachycardia), or a drop in blood pressure.
Serology refers to measurements of serum substances (markers) present in the blood which may predict the presence of tumor. The most commonly used marker is the serum CA19-9, which tends to be elevated in patients with bile duct cancer. However, this marker is not specific to bile duct cancer. It can be elevated in patients with other types of cancer and in patients without cancer. It is therefore not a very good screening test for the general public.
This is a tumor marker for bile duct cancer that is measured through a blood test. It is useful in assisting with an initial diagnosis. However, it is more useful in measuring the effectiveness of cancer treatment by studying the patient's CA19-9 levels over time.
In general, before surgery, the higher the CA19-9 level is (normal CA 19-9 level is 40 units per milliliter), the larger the tumor is and the less chance that the tumor is resectable. For the purposes of evaluating treatment, a decreasing or stable CA19-9 level generally indicates an improved prognosis and an increasing level indicates the progression of disease.
Currently, there are not sufficiently accurate diagnostic blood tests for bile duct cancer. Very few cancers, such as prostate and liver cancers, can be confidently diagnosed solely on the basis of blood test results. Perfecting a suitable blood test for bile duct cancer is an area of active research because it would enable screening for individuals considered at-risk.
Accuracy:
CA19-9 is elevated in the blood of about 90% of individuals with bile duct cancer. Other blood tests such as CEA can be used in combination with CA 19-9 to improve the accuracy of the test. Supplemental imaging studies and tissue samples are required with CA19-9 levels for a definitive diagnosis.
CA19-9 can be used to track treatment progress of previously diagnosed bile duct cancer patients. This blood test in conjunction with periodic CT scans will show whether the cancer is in remission or is continuing to grow.
Results:
If your doctor suspects bile duct cancer, an abnormal CA 19-9 blood level will increase the suspicion. However, there are benign diseases of the bile ducts and pancreas that occasionally result in elevated CA 19-9 levels. For this reason CA 19-9 is not considered a diagnostic test.
Pathology Tests
Pathology is the gold standard for the diagnosis of cancer. The diagnosis can sometimes be made by cytopathology, the study of individual cells spread into a thin layer onto glass microscopic slides.
Bile duct brushings can be performed through an endoscope (a special scope which is inserted into the mouth and passed into the first portion of the intestine) to detect malignant cells. If a mass is present, fine needle aspiration of it can be performed; this involves guiding a thin needle into the lesion, and gently sucking out cells for microscopic examination. These procedures have the benefit of not requiring an operation or general anesthesia.
A method to biopsy, obtain cells, for examination under the microsope.
FNA, performed in conjunction with a CT or MRI imaging, enables pathologists to determine the nature of a suspicious biliary tract abnormality. Procedure:
It is a surprisingly safe procedure that involves passing a small needle directly through the skin or through an endoscope. The CT or MRI imaging allows the doctor to see where the needle is going. This is because the needle used has a very small bore. This sometimes means that the small amount of tissue obtained is insufficient for the pathologist to establish a diagnosis.
Accuracy:
A diagnosis of biliary cancer based on a FNA is highly accurate, approaching 99%. However, it is only between 50-70% accurate in determining whether the cancer is benign or malignant.
Because the amount of tissue obtained is so small, the absence of malignant cells in the sample cannot exclude the possibility of malignant disease altogether.
Risks:
Complications such as bleeding or infection occur very rarely, less than 1% of patients.
Note:
Another technique used to obtain cells from the biliary tree for examination is bile duct brushing. In this procedure, through an endoscope, a brush is used to remove cells from the inside of the bile duct. These cells are smeared onto a slide and examined under the microscope.
Biopsy of the biliary tract is the more common means of detecting these tumors. Sometimes the biopsies can be performed through the endoscope; other times exploratory laparotomy, in which the surgeon makes an incision in the abdominal wall and enters the abdomen, is performed, under general anesthesia.
Types of Cancers +
More than 80% of all cancers of the gallbladder and bile ducts are carcinomas: tumors that arise in the epithelium (or surface lining).
Because most of the carcinomas produce small spaces (called glands), they are more specifically classified as "adenocarcinomas." Another term specifically used for these carcinomas is "cholangiocarcinoma" because of their origin from the biliary tract. Most biliary tract adenocarcinomas are highly invasive cancers that penetrate deeply into the walls of the bile duct or gallbladder. A smaller proportion of these adenocarcinomas tends to grow superficially into the open spaces (lumen) of the biliary tract as frond-like, "papillary" tumors. These papillary tumors are less likely to invade deeply, and therefore tend to have a better prognosis. Other more rare carcinomas of the biliary tree include small cell (neuroendocrine) carcinoma, and adenosquamous carcinoma.
Other tumor types rarely affect the biliary tract. Rare cases of malignant melanoma, a tumor that usually arises from the skin, and malignant lymphoma, that usually arises in the lymph nodes, can originate from the biliary tract or its surrounding tissues. It is important to distinguish these cancers from usual biliary carcinomas, since their treatment is different. Children almost never develop carcinomas of the biliary tree. The most common malignant tumor of the biliary tree in children is rhabdomyosarcoma, a tumor of the wall of the extrahepatic bile ducts (not its lining) which forms primitive skeletal muscle.
Biliary tract carcinomas are also often separated by location into carcinoma of the gallbladder and carcinoma of the extrahepatic (outside the liver) and intrahepatic (inside the liver) bile ducts.
Gallbladder carcinoma is twice as common as carcinoma of the extrahepatic bile ducts (5000 cases per year versus 2500 per year in the USA). Patients are usually in their 60's when they first show signs of disease, and there is a slight female predominance. This likely relates to the fact that the main risk factor for gallbladder carcinoma is gallstones (cholelithiasis), and these are more common in females. Gallstones are present in over 80% of gallbladders containing gallbladder carcinoma. The risk of developing carcinoma is increased if the stones are large and symptomatic, so these gallstones are generally removed prophylactically (for the purpose of preventing subsequent cancer) by surgery. The risk to each individual patient with asymptomatic gallstones is small; therefore, not all patients with gallstones necessarily need to have them removed.
Other risk factors for gallbladder cancer include:
Calcification of the gallbladder wall, which is often associated with gallstones and creates a "porcelain gallbladder" when severe
Benign polyps (noncancerous growths of the surface epithelium) of the gallbladder
Chronic bacterial infections of the biliary tract, which can predispose to gallbladder carcinoma, particularly in Asia, where gallstones are infrequent
Carcinoma of the extrahepatic and intrahepatic bile ducts is slightly more common in males, and patients usually present in their 50's. Risk factors include:
History of Primary Sclerosing Cholangitis (PSC) -- this is thought to be an autoimmune disorder, one in which the body's own inflammatory cells attack the bile ducts. PSC causes progressive scarring and narrowing of the bile ducts, which block bile from reaching the intestines. Many patients eventually develop liver failure, necessitating liver transplant. 10-20% of patients with PSC will develop bile duct carcinoma. Walter Payton, the Chicago Bears Hall of Fame football player, appears to have died from a bile duct cancer which developed after he was diagnosed with PSC. It is thought that the progressive epithelial injury and subsequent regeneration predisposes patients with PSC to carcinoma. More than half of patients with PSC have a history of another autoimmune disorder, idiopathic inflammatory bowel disease. This is most often ulcerative colitis.
Congenital abnormalities (abnormalities one is born with) of the bile ducts -- these include choledochal cysts (dilation of the common bile duct) and Caroli's disease (dilation of the intrahepatic bile ducts). It is thought that prolonged sludging of bile in these dilated spaces and subsequent infection predispose patients to carcinoma, again through progressive epithelial injury and repair. The overall lifetime risk of cholangiocarcinoma in these patients is 10%.
Benign tumors of the bile ducts -- A major risk factor is biliary papillomatosis, which refers to multiple papillary tumors diffusely involving the bile ducts. These may progress to invasive carcinoma.
Hepatobiliary parasitic infection -- these cases are most often seen in the Far East and include Clonorchis sinensis (most prevalent in Japan, Korea, Vietnam) and Opisthorchis viverrini (most prevalent in Thailand, Laos, Malaysia). Clonorchis is acquired when humans eat fresh water fish that harbor the Clonorchis cyst. The cysts develop into flukes (flatworms) in the friendly confines of the human intestine, and ascend from the duodenum (the first part of the intestine) into the common bile duct where they mature. The worms grow to be approximately 1 cm in length, and have a sucker that allows them to attach to the bile duct epithelium. Constant irritation of the biliary tract epithelium leads to epithelial damage, denudation (loss of the epithelial lining) and regeneration with fibrosis (production of collagen, or scar tissue). Carriage of this worm imparts a 25-50-fold risk of developing biliary tract carcinoma.
Toxic exposures -- thorium dioxide (Thorotrast), used as a contrast dye in radiologic procedures between 1930-1950, has been shown to promote cancers in the liver and bile ducts.
Treatment +
Surgical removal (resection) is currently the only hope for a cure for biliary tract carcinoma. These operations are difficult, and the most experienced surgeons generally obtain the best outcomes. At The Johns Hopkins Hospital, we have multiple surgeons with a strong interest in treating cancers of the gall bladder and bile duct. These include the Chairman of Surgery, Dr. John Cameron, Dr. Kurtis Campbell and Dr. Richard Schulick, all of whom have extensive experience operating on the extrahepatic and intrahepatic bile ducts, and gallbladder. Dr. Michael Choti is a surgeon here at Hopkins with extensive experience operating on the intrahepatic tumors. The location of the tumor dictates which operation will be performed, as detailed below.
Gallbladder cancers are treated by resection (surgical removal) of the gallbladder (cholecystectomy). Low stage tumors can be resected with a minimally invasive procedure called "laparoscopic cholecystectomy". Here, the surgeon operates through small finger-sized openings made in the abdomen. A camera and surgical instruments mounted on probes are inserted through the small openings. When the tumor is more advanced, an open cholecystectomy is performed in which the surgeon removes the gallbladder, a portion of the adjacent liver, and regional lymph nodes. Here, a standard larger abdominal incision is made.
Bile duct cancers within the liver (Intrahepatic cholangiocarcinomas) are treated by segmental resection of a portion of the liver. Occasionally, complete removal of the liver (hepatectomy) with liver transplantation will be attempted.
Bile duct cancers near the confluence (joining) of the bile ducts (perihilar cholangiocarcinoma) are treated differently depending upon how extensive the tumor is. Tumors confined below the right and left hepatic ducts are treated with resection of the extrahepatic bile ducts, gallbladder, and lymph nodes. Tumors that extend above the duct confluence may require resection of a lobe of the liver.
Distal bile duct cancers (those near the ampulla of Vater) are treated with a Whipple resection, which is a resection of the proximal duodenum (first portion of the small intestine), head of the pancreas, common bile duct, and gallbladder. The Whipple procedure is the same operation performed for cancers of the head of the pancreas. More Whipple resections are performed at The Johns Hopkins Hospital than at any hospital in the world.
If the tumor cannot be removed surgically, bypass procedures may be performed to prevent obstruction of the gastrointestinal and biliary tracts, and to relieve the patient's symptoms.
Patients with bile duct cancer most often become symptomatic when the cancer obstructs (blocks) the drainage of bile. Because bile cannot be excreted into the bowel, the bilirubin pigments accumulate in the blood, causing jaundice (yellowing of the skin and the whites of the eyes) in 90% of patients. The jaundice is usually associated with itching of the skin (also called "pruritus"). The body compensates partially and excretes some of this bilirubin via the urine, so patients may have dark (cola colored) urine. Because bile cannot reach the intestine, the patient's stools become white (clay colored).
Other symptoms result from inflammation secondary to tumor obstruction. Patients with gallbladder cancer may have pain in the right upper portion of the abdomen. This pain is a result of inflammation of the gallbladder (cholecystitis) due to blockage of the cystic duct. In fact, approximately 1% of patients who undergo cholecystectomy (surgical removal of the gallbladder) for suspected cholecystitis prove to have unsuspected gallbladder carcinoma. Distal bile duct tumors near the ampulla of Vater, the point at which the bile drains into the bowel, obstruct the pancreatic duct and lead to inflammation of the pancreas (pancreatitis).
The anatomy of the biliary tree is a little complicated, but it is important to understand. The liver's cells (hepatocytes) excrete bile into canaliculi, which are intercellular spaces between the liver cells. These drain into the right and left hepatic ducts, after which bile travels via the common hepatic and cystic ducts to the gallbladder. The gallbladder, which has a capacity of 50 milliliters (about 5 tablespoons), concentrates the bile 10 fold by removing water and stores it until a person eats. At this time, bile is discharged from the gallbladder via the cystic duct into the common bile duct and then into the duodenum (the first part of the small intestine), where it begins to dissolve the fat in ingested food.
Bile production and recirculation is the main excretory function of the liver. Tumors that obstruct the flow of bile from the liver can also impair other liver functions. Therefore, it is necessary to understand these other functions to understand the symptoms that these tumors can cause. These include:
An improvement on the standard (transabdominal) ultrasound.
