Bile duct cancer

What is bile duct cancer (cholangiocarcinoma)?

What is bile duct cancer (cholangiocarcinoma)?

The bile ducts within the liver come together like the tributaries of a river, to form a right-sided duct (draining all the bile from the right lobe) and a left-sided duct (draining the left lobe). These two then join to form what is called the common bile duct, which emerges from the under surface of the liver, and is roughly the thickness of a drinking straw. The gall bladder (a pear-shaped bag) hangs off the bile duct at this point, just after it has emerged from the liver. The bile duct then runs through the pancreas for a bit, and enters the duodenum (a part of the intestine) where the bile mixes with the food. The pancreatic duct, which drains the digestive juice from the pancreas, also empties into the duodenum at the same place. Tumours of the biliary system can be divided into those of the bile ducts within the liver (i.e. intrahepatic), the bile duct outside the liver (i.e. extrahepatic), and tumours of the gall bladder. The term used for bile duct cancer is cholangiocarcinoma. Biliary cancers account for 10-15% of all primary hepato-biliary cancers and 3% of all gastrointestinal cancers worldwide. High-risk areas include Thailand, Japan, Korea, Eastern Europe (European Russia, Czech Republic, Poland), and American Indians. In most areas, biliary tumours (except gall bladder cancers) have a slightly higher incidence in men than women.

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What causes bile duct cancer?

What causes bile duct cancer?

Risk of bile duct cancer is increased by fibrocystic disease of the liver (called Caroli’s disease), choledochal cysts (i.e. bile duct cysts) and abnormalities of the junction of the pancreatic and bile ducts. Environmental factors like exposure to toxins such as Thorotrast (a radiologic material used in the 1950s), and industrial toxins such as dioxins and polyvinyl chloride also increase the risk. Liver fluke infestations in the Far East are associated with the high incidence of intrahepatic cholangiocarcinomas in those areas. Smoking and alcohol consumption further increases this risk in these ethnic groups. Hepatitis C seems to have a link. Underlying cirrhosis increases the risk of intra-hepatic cholangiocarcinomas. In the West, the best known predisposing factor is primary sclerosing cholangitis (PSC), a chronic inflammatory disease of the bile ducts, which carries a life-time cancer risk of 9-23%.

Ultrasound picture of a choledochal cyst
Ultrasound picture of a choledochal cyst (i.e. a balloon-like swelling of the bile duct) in a 35-years old woman. Over her lifetime, she would have a higher-than-average risk of developing a bile duct cancer
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How does bile duct cancer spread?

How does bile duct cancer spread?

The tumours at the junction of the right and left ducts are referred to as Klatskin tumours or hilar cholangiocarcinoma (i.e. at the hilum or the stalk of the liver). Cholangiocarcinomas may form a mass, or grow in an infiltrative manner around the bile duct. The extent of spread is described in terms of the TNM (Tumour-Node-Metastasis) system, but this can only be done accurately following surgery and pathological examination of the resected specimen. Bile duct tumours spread to the lymph glands (nodes) in the vicinity, and also along the inner lining of the bile duct and along the nearby nerves. Untreated, most patients with bile duct cancer die within 6 months to a year of diagnosis from a combination of local tumour spread and cholangitis (infection in the bile ducts). Direct spread to the liver is the rule, but tumour can show up in bile ducts well away from the primary and we do not know if these are separate primary tumours or secondaries. In rare cases, distant spread occurs to bone and lymph nodes further away.

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What are the symptoms and signs of bile duct cancer?

What are the symptoms and signs of bile duct cancer?

Cholangiocarcinoma rarely occurs in individuals under the age of 40. Patients usually present with painless jaundice and itching, dark urine and pale stools. This is a scenario that doctors refer to as obstructive jaundice. Blockage of the bile flow means that little or no bile gets into the gut (hence the pale stools), and the bile pigment spills into the blood circulation (hence the yellow colour of the skin and eyes) and into the urine (which looks dark brown). We do not know why people itch.

Abdominal pain may be present in up to 40% of patients. Cholangitis (biliary infection) may occur and is suggested by pain in the right side of the abdomen, fever and shivering. Weight loss and loss of appetite are late symptoms. A swollen liver may be felt in up to 75% of patients and ascites (abdominal fluid) may be seen in advanced tumours. Intrahepatic cholangiocarcinoma needs to be considered as a possibility in patients presenting with a liver mass, where the other possibilities will include a primary hepatoma (HCC) and or liver metastasis. Patients known to have primary sclerosing cholangitis who develop cholangiocarcinoma may present with rapid deterioration in their physical condition and worsening jaundice. Occasionally, patients who have no symptoms may be identified during tests for unexplained increases in liver enzymes.

The differential diagnosis for cholangiocarcinoma includes malignancy of the pancreatic head and duodenum, chronic pancreatitis, stones in the common bile duct, primary sclerosing cholangitis and other forms of cholangitis, injuries to the bile duct, parasitic infestations and lymph node metastases at the liver base. Rarely hepatitis can masquerade as obstructive jaundice.

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What tests are done to diagnose bile duct cancer?

What tests are done to diagnose bile duct cancer?

Obstructive jaundice causes a rise in the serum bilirubin and several of the liver enzymes. Two tumour markers called CA 19-9 (Carbohydrate antigen 19-9) and CEA (Carcino embryonic antigen) may be elevated in cholangiocarcinoma, but they are also raised in other cancers including pancreas, colon, stomach and gynaecological cancers, and obstructive jaundice from other causes.

Ultrasound (US) is the initial scan amd may show up the tumour and the swollen bile ducts upstream. It may also suggest alternative diagnoses such as gallstones.

CT (computed tomography) scan will show bile duct swelling and mass lesions greater than 1 cm. As well as tell if lymph nodes are enlarged or any major blood vessels are involved.


MRCP picture showing hepatic ducts.
MRCP picture showing swollen right and left hepatic ducts, with a tumour causing a blockage at the confluence

MRI (Magnetic resonance imaging) is another useful scan that yields information similar to CT, but also gives three-dimensional reconstruction of the bile ducts (called MRCP). This can provide a roadmap for the biliary anatomy above and below the tumour.

ERCP (Endoscopic retrograde cholangiopancreatography) refers to an endoscopic procedure. A flexible endoscope is passed down the gullet into the stomach and then into the intestine, and contrast medium (a dye that shows up on x-rays) is injected into the common bile duct. This shows up the level and extent of the blockage. A plastic or soft metal tube (called a stent) can then be pushed up through the blockage, to allow the bile to flow again. Bile samples, biopsy samples and brushings from the blockage can be sent to the pathology laboratory, to be checked for the presence of cancer cells. PTC (percutaneous transhepatic cholangiography) is a different procedure but with a similar intent. It involves needle puncture of the skin over the liver, and then of the liver substance. A fine tube is passed into the bile duct, under ultrasound guidance, and a stent can then be pushed across the blockage (but from above, in this instance). Again, bile samples, biopsies and brushings can be taken. The choice between PTC or ERCP is usually determined by local expertise, availability, and failure of one or the other technique, usually ERCP. PTC is preferable for higher strictures and often a combination of both procedures is required. These invasive techniques carry the risk of procedural complications including bleeding, biliary leakage, pancreatitis, cholangitis and duodenal perforation.

Picture taken at ERCP showing a cancerous obstruction high up in the common bile duct
Picture taken at ERCP showing a cancerous obstruction high up in the common bile duct

Laparoscopy (inspection of the abdominal cavity with a camera inserted through a keyhole incision) can sometimes detect small tumours and liver secondaries missed on other scans, though it is less accurate for blood vessel or lymph node involvement. The combination of laparoscopy with laparoscopic ultrasound may prevent an unnecessary attempt at surgery in some patients.

Histological or cytological diagnosis (i.e. confirming the presence of cancer cells in a tissue sample) is not mandatory before surgical exploration.

PET (Positron emission tomography) scanning can detect cholangiocarcinoma as well as the presence of distant spread, but its use is not routine.

EUS (endoscopic ultrasound) increasingly plays a role in the diagnosis of cholangiocarcinoma and can also guide fine needle aspiration of a cell sample.

© 2016 hpblondon.com

What is the treatment of bile duct cancer?

What is the treatment of bile duct cancer?

The treatment options for cholangiocarcinoma are determined by stage of the disease in terms of tumour size and extent, involvement of the major blood vessels flowing into the liver, and the presence or absence of metastases.


surgical_resection_diagram

Surgical resection

Complete surgical removal of the tumour with clear margins offers the only possible cure for cholangiocarcinoma. Unfortunately many patients present with unresectable disease at diagnosis. The few patients considered suitable for surgery must be medically fit, with no metastases and have local disease that can be resected with clear margins. Patients with poor physical health, major cardiovascular disease or advanced liver cirrhosis are not candidates for surgery. The presence of infection, severe jaundice and malnutrition also predict poor outcomes but may be corrected to an extent prior to surgery. Draining the blocked biliary system (by ERCP or PTC) prior to surgery has not been shown to significantly decrease morbidity or mortality. But it should be considered in all patients with severe jaundice (who run the risk of liver failure) and in those with biliary infection (cholangitis). If it is felt that the proposed operation will remove over 75% of the liver, and not leave the patient with a sufficient remnant liver, then selective portal vein embolisation (PVE) can be done. You can read more about PVE in the section on Liver tumours. PVE can induce growth of the future liver remnant and reduce the risk of liver failure following surgery.


The type and extent of surgery depends on the location of the cancer within the liver or the biliary tract. The Bismuth classification (shown in the diagram above) is a practical and commonly used surgical classification of bile duct tumours at the junction of the right and left ducts. It is based on which ducts are involved and the extent to which they are involved.  Cancers of the common bile duct (Bismuth Type I and II) require removal of the common bile duct and the regional lymph glands, with creation of a join between the right and left bile ducts on the one hand and the bowel on the other (so that bile can continue to flow into the bowel). The term used for this join is a Hepatico-jejunostomy. Tumours involving the confluence (Bismuth Type III) require, in addition, removal of a part of the liver. Type IV tumours – in the rare event of one being resectable - need an extended liver resection to achieve clear margins. Cholangiocarcinomas in the lower part of the bile duct, where it passes through the pancreas, should be managed with a pancreatoduodenectomy (also known as a Whipple operation).

In most Western hospitals around 15-35% of cholangiocarcinomas prove resectable, though adoption of a more aggressive policy in terms of en-bloc resection with vascular reconstruction (i.e. resecting and repairing major blood vessels involved by the tumour) can lead to more resections. The adoption of an aggressive resection policy correlates with a significant trend towards prolonged survival, with 40-60% 3-year survival rates in most series. However, the more extensive resections are associated with a higher mortalility of around 10% and significant postoperative morbidity upto 40%.

The use of liver transplantation for unresectable hilar cholangiocarcinoma is controversial because of the high recurrence rates, and decisions about individual patients need careful consideration.

Adjuvant therapy

Neoadjuvant chemotherapy (i.e. chemotherapy given prior to surgery with the intention of shrinking the tumour down) has been shown in some studies to increase the chances of a successful resection, but is often limited by the presence of obstructive jaundice and the poor physical condition of many patients. Adjuvant chemotherapy (i.e. chemotherapy given after an operation, with the intent of mopping any remaining cancer cells in the system) has been tried. The drugs used have been 5Fluorouracil (5FU) alone or in combination with methotrexate, cisplatin, mitomycin C, leucovorin or interferon alpha. Adjuvant radiotherapy in the form of external beam irradiation with or without iridium-192 implants have also been used. These have not been convincingly shown to prolong survival, reduce recurrence or improve quality of life, if the cancer has been completely removed. There may possibly be a benefit for adjuvant radiotherapy alone or with chemotherapy for patients who still have residual cancer after their surgery. Adjuvant therapy is presently not routinely recommended outside the setting of clinical trials.

Biliary stenting

In patients with nresectable cholangiocarcinomas, endoscopic or percutaneous stenting for biliary drainage seeks to relieve jaundice and itching, prevent cholangitis, avoid liver failure and improve quality of life. Both plastic and self-expanding mesh metal stents are available for biliary drainage. Choice of stent must be tailored to the individual patient. Overall, self-expanding metal stents offer the more cost-effective treatment for patients likely to survive longer than 3-6 months. Though more expensive, they have a larger diameter and stay open longer (6-12 months) compared to plastic stents (which often get clogged in 3-6 months). Tissue confirmation of cancer is deemed essential prior to insertion of metal stents, which tend to get embedded in the bile duct wall and can only be removed at operation.

Surgical palliation

A surgical biliary-enteric bypass, i.e. creation of a join between the biliary system (above the level of the blockage) and the bowel, can be performed to relieve jaundice, even if the tumour itself cannot be resected. This is particularly relevant for patients who undergo an operation but are then found at the time of the operation to have unresectable disease. Coeliac plexus blockade can be considered for severe pain.

Palliative chemotherapy and radiotherapy

Palliative chemotherapy using Gemcitabine in combination with Cisplatin has shown some benefit in terms of treatment responses. Survival benefit from conventional radiotherapy for palliation is unproven.

Photodynamic therapy

Photodynamic therapy (PDT) involves the intravenous administration of a photosensitiser substance such as sodium porfimer. This localises preferentially in tumour tissue over the next 24-48 hours. After that an endoscope is passed into the gut, and a laser light is shone upon the tumour. This activates the porfimer, generating oxygen free radicals and causing cancer cell death. There was some early evidence that biliary stenting combined with PDT (versus stenting alone) may lead to increased survival and a better quality of life. But enthusiasm for this treatment has waned after further trials did not show benefit; further studies of PDT in combination with chemotherapy or radiotherapy or both are required. Other local ablation strategies such as radio frequency ablation and ethanol injection are unproven.

© 2016 hpblondon.com
These treatment options are described here in a very general sense, and individual patients should discuss their treatment with their own medical team.
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