Gallbladder and Bile Duct Cancer

About the Disease

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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 +

Obstruction of bile ducts 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).

inflammation causes acute pain 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:

  1. 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).
  2. 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.)
  3. 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).
  4. Protein and miscellaneous components

overview of anatomy 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

duct anatomy duct anatomy

Diagnosis +

Many types of tests are used to help diagnose bile duct cancer. These can be grouped as radiology, serology, and pathology.

Click the test name for detailed information.

Radiology Tests

  • Ultrasound
  • Computed Tomography (CT)
  • MRI
  • Endoscopic Retrograde Cholangio-Pancreaticography (ERCP)

Serology Tests

  • CA19-9

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.

  • Fine Needle Aspiration (FNA)
  • Biopsy

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.

Perihilar Illustration Postperihilar Illustration

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.

Whipple Specimen Illustration Post-Whipple Illustration

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.