Bile Duct Cancer (Cholangiocarcinoma)

What is bile duct cancer?

Bile duct cancer is a malignant tumour arising from the bile ducts that carry the bile produced in the liver to the bowel. Its medical name is cholangiocarcinoma.

The bile ducts begin as small channels inside the liver, join together progressively, and form the main bile duct outside the liver. So bile duct cancer is not a single kind of disease: where in the ducts the tumour develops affects its symptoms and the treatment that can be given considerably.

Bile duct cancer is an uncommon cancer.

What kinds of bile duct cancer are there?

It is divided into three main groups according to where the tumour lies.

1. Intrahepatic cholangiocarcinoma

This arises from the bile ducts within the liver.

It may be seen as a mass in the liver and, because of certain features, can be confused with other liver tumours.

2. Perihilar cholangiocarcinoma

This develops in the region where the right and left main bile ducts join at the exit from the liver.

Tumours in this region are called hilar or perihilar cholangiocarcinoma. The term “Klatskin tumour” is also used for some tumours in this region.

Because it can obstruct the flow of bile, jaundice may be an important finding.

3. Distal cholangiocarcinoma

This arises from the part of the main bile duct near the pancreas and the duodenum.

Tumours forming in this region can also block the bile duct and lead to jaundice.

Cancer of the head of the pancreas and distal bile duct cancer are different diseases, but because the regions they lie in are close together they can produce similar symptoms.

Why does bile duct cancer develop?

In most patients no definite cause can be established.

Even so, certain diseases that cause long-standing inflammation and damage in the bile ducts can increase the risk.

Some of the most important risk factors are:

• Primary sclerosing cholangitis (PSC),
• Certain congenital diseases of the bile ducts,
• Choledochal cysts,
• Certain chronic biliary diseases,
• Liver fluke infections seen in some regions,
• Advancing age.

But cholangiocarcinoma can also develop in people with none of these risk factors.

Why does PSC matter?

Primary sclerosing cholangitis is a disease that can cause chronic inflammation, scarring and strictures in the bile ducts.

The risk of developing cholangiocarcinoma is markedly higher in people with PSC than in the general population.

For this reason, new or increasing jaundice, weight loss, or a marked new stricture in the bile ducts should be assessed carefully in patients with PSC.

But finding a biliary stricture in a patient with PSC does not automatically mean cancer.

What are the symptoms of bile duct cancer?

The symptoms vary with where the tumour lies.

In tumours that obstruct the bile duct, one of the most important symptoms is jaundice.

Patients may have:

• Yellowing of the eyes and skin,
• Dark urine,
• Pale stools,
• Itching,
• Unexplained weight loss,
• Loss of appetite,
• Weakness,
• Abdominal pain or discomfort,
• Nausea.

Intrahepatic tumours arising from the small bile ducts within the liver may not completely obstruct a bile duct at first, and so can appear without jaundice.

Why does jaundice develop?

If a tumour in the bile duct prevents bile passing into the bowel, bilirubin begins to build up in the blood.

The result may be:

obstruction of the bile duct → a rise in bilirubin → yellowing of the eyes and skin → dark urine + pale stools + itching.

Jaundice is an important symptom of bile duct cancer, but not every jaundice means cancer.

Stones in the bile duct and benign biliary strictures can produce exactly the same picture.

Does bile duct cancer cause pain?

It can, but pain is not necessarily present.

In some tumours obstructing the bile duct in particular, the first finding may be painless jaundice.

In tumours developing within the liver, pain or discomfort may be felt in the right upper abdomen.

How is bile duct cancer diagnosed?

The diagnosis is not made with a single test.

The patient’s symptoms and blood tests are assessed first. Various imaging and endoscopic methods may then be used according to where the tumour lies.

These include:

• Ultrasound,
• Computed tomography (CT),
• Magnetic resonance (MR),
• MRCP,
• EUS,
• ERCP.

What is the role of MRCP?

MRCP is an MR method that can image the bile and pancreatic ducts in detail without any procedure.

It is very useful in showing, in the bile duct:

• Where the stricture is,
• How long it is,
• Whether the bile ducts above the stricture are dilated,
• The general anatomy of the bile ducts.

But a biopsy cannot be taken directly with MRCP.

Why is an EUS done?

Endoscopic ultrasound (EUS) allows detailed assessment of the parts of the bile duct near the pancreas in particular, of the pancreas itself, and of the surrounding lymph nodes.

Where necessary, a tissue sample can be taken from a suspicious mass or lymph node during EUS.

It matters that the method of taking the biopsy is planned carefully according to where the tumour lies.

What is the role of ERCP?

Where bile duct cancer is suspected, ERCP is today not a procedure done for imaging alone.

In obstructed bile ducts in particular, ERCP allows:

• The stricture to be assessed,
• Brush cytology or a biopsy to be taken,
• A stent to be placed to restore the flow of bile.

So ERCP can be used both for diagnostic sampling and for treatment.

What is cholangioscopy?

In some patients, very fine endoscopic systems allowing the inside of the bile duct to be imaged directly can be used during ERCP.

This method is called cholangioscopy.

It can help the suspicious area to be seen directly and, where needed, a targeted biopsy to be taken from it.

It can be useful particularly in certain biliary strictures of unexplained cause.

Does a biopsy always give a definite answer?

Not always.

Taking an adequate tissue sample from a bile duct tumour can be difficult in some situations.

For this reason a negative brushing or biopsy result at ERCP does not always definitely exclude the disease where the clinical and imaging findings strongly suggest cancer.

Repeat sampling by a different method may be carried out where needed.

What is CA 19-9?

CA 19-9 is a tumour marker that may be raised in some cancers of the bile ducts and the pancreas.

But it does not on its own establish a diagnosis of cancer.

CA 19-9 can be markedly raised without cancer being present, particularly when the bile duct is obstructed or where there is cholangitis.

For this reason:

a high CA 19-9 is not definite cancer.

Equally, a normal CA 19-9 does not entirely exclude cancer.

Why does staging matter in bile duct cancer?

Once the diagnosis is made, how far the disease has spread is assessed.

What is investigated is the tumour’s:

• Site and extent within the bile ducts,
• Relationship to the liver and the surrounding tissues,
• Whether it affects the large blood vessels,
• Spread to the lymph nodes,
• Whether there are metastases in distant organs.

All of this determines the choice of treatment.

Can bile duct cancer be operated on?

Yes. Surgical treatment is possible in suitable patients.

Surgery is one of the most important treatment options for long-term control of the disease in bile duct cancers that can be removed completely.

But the operation carried out varies with where the tumour lies.

In intrahepatic tumours, the part of the liver containing the tumour may need to be removed.

In perihilar tumours, more extensive operations may be needed, in which certain parts of the liver are removed together with the bile ducts.

In distal bile duct cancers, a Whipple operation, in which the head of the pancreas is also removed, may be carried out in some patients.

It matters that these operations are done in experienced centres.

Can every patient have an operation?

No.

The tumour’s relationship to the important blood vessels, its extent within the liver, whether there are metastases in distant organs, and the patient’s general state of health are all assessed.

Where the disease cannot be removed completely, other treatment methods are used.

Is chemotherapy used?

Yes.

Chemotherapy may be used:

• After an operation, to reduce the risk of the disease returning,
• In locally advanced disease that cannot be operated on,
• In disease that has spread to other organs.

Today, alongside chemotherapy, immunotherapy and targeted treatments have also become important in the treatment of cholangiocarcinoma in suitable patients.

Why do molecular and genetic tests matter?

Investigating certain molecular characteristics of the tumour tissue has become steadily more important, particularly in advanced bile duct cancers.

Some tumours may carry specific genetic changes that can affect treatment.

Finding molecular changes such as FGFR2, IDH1, HER2 or BRAF, or features such as MSI/dMMR, in particular patients can open up different treatment options.

Because the same change is not present in every patient, treatment can be individualised according to the molecular characteristics of the tumour.

Why is a stent placed in the bile duct?

When a tumour obstructs the bile duct, bile builds up in the liver.

In suitable patients, the flow of bile can be restored using ERCP or other drainage methods.

A plastic or metal stent can be placed at the narrowed area during ERCP.

The stent:

opens the obstruction → restores the flow of bile into the bowel → helps the bilirubin to fall → helps the jaundice and the itching to lessen.

But a stent is not a treatment that removes the cancer. It is a procedure directed at relieving the obstruction of the bile duct.

Can cholangitis develop?

Yes.

Bacterial infection can develop in obstructed bile ducts. This is called acute cholangitis.

The combination of:

fever + jaundice + abdominal pain

matters in particular.

If shivering, low blood pressure or a change in consciousness also develops, the situation may be more serious.

Cholangitis may require urgent antibiotic treatment and, in some patients, urgent drainage of the bile duct.

Is it possible to prevent bile duct cancer?

It is not possible to prevent most cholangiocarcinomas entirely.

But regular follow-up of the conditions that pose a high risk, such as PSC and certain congenital diseases of the bile ducts, is important.

A new biliary stricture, jaundice or unexplained clinical change appearing in a patient at risk should be assessed without delay.

When should a doctor be consulted?

Assessment should be carried out particularly where there is:

• Newly developed jaundice,
• Marked darkening of the urine,
• The stool becoming pale,
• Itching of unexplained cause,
• Unexplained weight loss,
• Loss of appetite,
• Constant right upper abdominal pain.

If jaundice is accompanied by fever and shivering, emergency assessment may be needed for infection of the bile duct.

Remember

Bile duct cancer (cholangiocarcinoma) is a cancer arising from the bile ducts, which can show different characteristics according to where it lies.

The presence of a stricture or of jaundice in the bile duct does not on its own mean cancer. Stones in the bile duct and benign biliary strictures can produce very similar findings.

CT, MR/MRCP, EUS and ERCP are complementary methods in making the diagnosis. Taking a tissue sample where needed helps with the diagnosis.

The most important matter in treatment is establishing the site and stage of the disease and whether it can be removed completely by surgery. In advanced disease, alongside chemotherapy, immunotherapy and treatments targeted at the molecular characteristics of the tumour can today be used in some patients.

It matters that treatment is planned by a multidisciplinary team in which gastroenterology, hepatobiliary surgery, medical oncology, interventional radiology, radiology and pathology assess the patient together.