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Cholangiocarcinoma – 2015

UPDATED DECEMBER 2015

1. General information

1.1 What is the disease and how is it treated?

What is cholangiocarcinoma?
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma that arises from the epithelial cells of the bile ducts, which transport bile from the liver to the intestines. For this reason it is also referred to as bile duct cancer.
It accounts roughly for 20% of all primitive cancers of the liver. It is particularly widespread in Asian countries. It is more common among males, with a peak around the 7th decade of life.

How does cholangiocarcinoma manifest itself?
Typical signs and symptoms are: jaundice, pale-coloured stools, darkened urine, pain in the stomach area, itching, liver enlargement, weight loss, fever.

What are the causes of cholangiocarcinoma?
The causes of the disease are largely uncertain. It is known, however, that chronic inflammation and cellular damage of the bile ducts (resulting from obstruction of bile flow) are among the major factors responsible for CCA onset.

Is this a frequent type of cancer?
CCA is a rare cancer: there are about 1.5 cases every 100,000 people in Europe, with a higher occurrence among males.

How is it diagnosed?
First, through a clinical examination: after having looked for signs of jaundice, the doctor may feel a lump in the area, or an enlarged liver.
Blood tests may reveal the presence of substances indicating biliary obstruction (e.g., bilirubin), or tumour markers.
Various instrumental tests (ultrasound, CT scans, MRI scans, endoscopy) can help establish the diagnosis by “taking a look” at the bile ducts, pancreas, gallbladder, and liver.

How is it treated?
Surgery is the only potentially curative treatment option for cholangiocarcinoma. Following surgery, radiotherapy and chemotherapy are used to reduce the risk of CCA relapse and to delay or control cancer development and symptoms.
Radiotherapy and chemotherapy are also used to treat inoperable patients.

2. Cholangiocarcinoma: what is it, how does it occur, how is it diagnosed

2.1 What is cholangiocarcinoma?

Cholangiocarcinoma is a rare type of malignant tumour arising from the liver.
The liver is a very important organ, with a number of basic functions. Among them, the production of a special fluid, bile, which helps digestion by breaking down fats. In order to do its job, bile must reach the small bowel (intestine). Bile ducts are tiny canals which collect bile from the liver or gallbladder (where bile can be stored) and carry it to the small bowel.
CCA arises from the epithelial cells of the bile ducts.

Bile ducts
There are two main bile ducts in the liver, the right and left hepatic ducts. They join together just outside the liver to form the common hepatic duct. Another bile duct comes from the gallbladder. This is called the cystic duct. The hepatic duct and cystic duct join together to form the common bile duct.
The common bile duct then joins with the pancreatic duct and the combined ducts finally open into the small bowel, where bile is released.

Bile duct cancers are divided into 3 groups depending on where they develop in the biliary system (see figure 2 Professional area):

  • intrahepatic: this cancer develops within the liver and includes the right and left hepatic ducts and their smaller branches;
  • perihilar (hilar): this cancer grows just outside the liver where the right and left hepatic ducts meet;
  • distal: this cancer develops in the bile ducts close to the small bowel and the pancreas.
2.1.1 Disease stats

Frequency
CCA is a rare cancer, traditionally more widespread in South-Eastern Asia, although in the last years the number of new cases has been on the rise in Western Countries.
Each year, in Europe, about 1.5 persons out of 100,000 are diagnosed with a CCA (incidence). Most patients are older than 65, with a peak between 70 and 80 years of age. CCA is very rare under the age of 65.

Gender
The number of male patients is 40% higher than that of women affected.

Geographical distribution
The occurrence of the disease varies markedly worldwide, presumably reflecting differences in local risk factors and genetics. The highest known rate is in North-Eastern Thailand (>80/100,000 people), one of the lowest in Canada (0.3/100,000).

Prevalence
In Europe, about 30,000 people were living with a diagnosis of CCA at the beginning of 2008. Sixty-one percent of them were people who had survived 5 years or less after diagnosis (slightly more than 18,000 cases at the beginning of 2008).
Long-term survivors (i.e., people surviving 15 years or more after their CCA diagnosis) were few, due to poor survival rates for this type of cancer. In Europe, the estimated prevalence of long-term survivors is 0.5/100,000: about 2,600 cases, most of which can be considered cured.

Survival
Prognosis of cholangiocarcinoma is generally poor. In Europe, 5-year survival significantly improved during the period 1999-2007, from 13% to 15% (RARECAREnet project).
In Europe, according to the RARECAREnet project, 5-year survival, for cases diagnosed between 2000 and 2007, was 5% and 17% for intra- and extrahepatic ducts, respectively.
One-year survival for intrahepatic CCA was 25%, after that survival decreased markedly to 8% and 5% at 3 and 5 years after diagnosis. In extrahepatic CCA, outcomes fell less rapidly, from 48% at 1 year to 23% at 3 years. Five-year survival was 52% in patients aged 15-24 years, dropping dramatically to 19% in the 25-64 age group, and 11% in patients over 65.

2.2 Risk factors

Some people are at higher risk than others of developing certain diseases. This can be due to different risk factors. A risk factor is something that increases the chances of a person to contract a disease like cancer; however, a person who has one or more risk factors will not necessarily get sick.
Mostly, causes of CCA are not clear. However, in a minority of cases (approximately 10%) well-known risk factors and conditions, all of which cause a chronic inflammation of the bile ducts, are associated with the tumour.
Here are the main risk factors:

  • Primary sclerosing cholangitis (PSC): the disease arises from an inflammation that causes narrowing of the bile ducts and, ultimately, obstruction of the flow of bile, which then accumulates in the liver, damaging its cells. It affects more males than females, its onset is generally around 30-50 years of life. It is often associated with an intestinal inflammatory disease (e.g., Crohn’s disease). In Western countries, PSC is the most common disease associated with cholangiocarcinoma: every 1 or 2 out of 10 people with PSC will develop CCA.
  • Choledochal cysts: these are sacs that connect to the bile duct and fill up with bile. They grow slowly and can end up holding up to 2 litres of bile. The disease entails reflux and stasis of biliopancreatic secretions, formation of gallstones, and bacterial contamination. If cysts are not removed, up to 2 in 10 people will develop CCA.
  • Parasitic diseases: infestation with liver flukes, known as pyogenic cholangitis or Oriental cholangiohepatitis, is typical of oriental countries and is caused by the consumption of raw or undercooked fish containing adult worms. The disease can lead to cholangiocarcinoma in 8%-10% of cases.
  • Liver cirrhosis: this disease appears as a scarring of the liver due to continuous, long-term liver damage. The scar tissue stops the liver from working properly. It is often caused by alcohol abuse or infection with hepatitis C or B viruses, but sometimes also by rare metabolic diseases (e.g., haemochromatosis, Wilson’s disease).
  • Exposure to chemical agents (nitrosamines, dioxin, asbestos, thorotrast, radon) and radionuclides has been identified as a risk factor for cholangiocarcinoma.

2.3 What are the symptoms of cholangiocarcinoma?

Symptoms vary depending on where the cancer is in the bile ducts. Cancers that start in the liver bile ducts (intrahepatic bile duct cancer) often don’t cause any specific symptoms until they are more advanced.
Symptoms also depend on the size of the tumour.
Patients with early stage disease are usually asymptomatic.

2.3.1 Symptoms

The following are the most common symptoms of CCA.

  • Jaundice: jaundice without pain is frequently an initial symptom of extrahepatic tumours (70%-90% of patients), while it is less common in patients with intrahepatic CCAs. When people have jaundice, their urine is darker than normal, while stools are pale; most people experience itchy skin.
  • Weight loss: many patients lose weight for no apparent reason; this is one of the most common symptoms with intrahepatic bile duct cancer.
  • Abdominal discomfort: a light pain in the right-hand side, just below the ribs, is a common symptom of CCA.
  • Swelling of the liver: sometimes the enlargement of the liver can give rise to a mass in the right upper abdomen.
  • Fever: it can be caused by an inflammation or an infection in the bile ducts.

If one or more of these symptoms are present and persist for more than a few days, it is important to report to the GP.

2.3.2 What centres to choose

Patients should look for centres with high expertise in the treatment of CCA.

2.4 Diagnosis

2.4.1 How is the disease identified as a CCA?

Diagnosing CCA can be a difficult task, in part because of its anatomic location, in part because of the absence, in most cases, of symptoms that may alarm people and drive them to the doctor. For these reasons, diagnosis requires a multidisciplinary approach, involving a series of clinical, laboratory, and imaging exams.

Clinical examination. This is the first step when a bile duct cancer is suspected. First, the GP will look at the patient’s skin and eyes and may prescribe urine and blood tests to check for jaundice. The doctor will also try to see if a lump can be felt in the area, or if the liver is enlarged.
Laboratory tests. Blood tests are needed in order to evaluate how well the liver works. High levels of bilirubin, alkaline phosphatase, and glutamyltransferase may indicate an obstruction in bile flow (i.e., cholestasis). Other tests may search for CEA and CA 19.9 tumour markers, substances that may be produced by bile duct cancer.
Diagnostic imaging. Tests such as ultrasound, CT, or MRI scans, and endoscopy can help in the diagnosis by “viewing” the bile ducts, pancreas, gallbladder, and liver from “outside” or “inside” the body.

  • Ultrasound scan. Sound waves are used to take pictures of internal parts of the body; in this case the bile ducts, pancreas, and liver are scanned in order to check for signs of cancer. The exam is painless.
  • Endoscopic ultrasound. An ultrasound scan from “inside” the body, this exam is performed by inserting a flexible tube (endoscope), equipped with a light, a camera, and a small ultrasound probe, down the patient’s throat. The picture obtained helps to see if there are cancerous areas and, if so, it can be used to guide a small needle to remove a sample of tissue (biopsy). Normally, patients are given a sedative (a medicine that makes them drowsy).
  • CT (Computerised Tomography) scan. A machine takes a series of X-rays of the body from different angles, then a computer puts them together, returning a very detailed picture of the inside of the part of the body being scanned. When looking for signs of CCA, a contrast medium is injected before starting the scan. This helps to better distinguish pathological tissues from healthy ones. The scan is painless.
  • MRI (Magnetic Resonance Imaging) scan. Magnetic waves are used to produce images of the internal organs of the body. The exam is painless.
  • MRCP (Magnetic Resonance Cholangiopancreatography) scan. It is a type of MRI giving detailed pictures of the pancreas, gallbladder, and bile ducts. Neither contrast mediums, nor sedatives are necessary. The scan is painless.
  • ERCP (Endoscopic Retrograde Cholangiopancreatography). Similar to a gastroscopy, it is performed by inserting a flexible tube (endoscope) carrying a light and a camera at the end, down the patient’s throat. It makes it possible to obtain complete imaging of the biliary ducts and also to remove any obstructions present. A dye can be used to better see if there is a narrowing or a blockage of bile ducts. It is an invasive exam.
  • PTC (Percutaneous Transhepatic Cholangiography). A catheter is inserted into the bile ducts, where a dye is injected. The manoeuvre is conducted under radiological guidance: the dye shows any blockages on X-ray. A biopsy can be taken during the test.
  • FDG-PET (FluoroDeoxyGlucose-Positron Emission Tomography). This imaging technique produces a three-dimensional image of functional processes in the body. It detects the radioactive signals emitted by a tracer introduced into the body. In this case FDG, an analogue of glucose, is used in order to reveal areas with higher than normal metabolic activity (detectable as an increase in glucose consumption by the cells), a sign of the presence of cancer cells.
  • Biopsy. It is used to take a sample of tissue from what seems to be an abnormal area at endoscopy; it requires the use of local or general anaesthesia.
2.4.2 Do these tests involve any risks for patients?

Generally, all of these exams are well tolerated. Endoscopy and biopsy may require the use of a local or general anaesthetic. CT, MRI, and ERCP may require the injection of a dye (or contrast medium) in order to obtain clearer images. PTC and FDG-PET always use dyes. Anaesthetics and contrast media could give rise to side effects.
ERCP, being an invasive manoeuvre, may give rise to various complications: the most common (it can happen in 1 out of 10 people) is pancreatitis.

3. How is Cholangiocarcinoma treated?

3.1 Which therapies are currently employed?

The type of treatment for CCA depends on different factors related both to the disease (cancer stage [see below], where in the bile duct it started, presence of metastases) and to the patient (general health, age, comorbidities).
Treatment may include surgery and medical therapies (radiotherapy and chemotherapy) which can be employed to cure the disease, to control or slow down the growth of cancer, and to control/relieve symptoms (palliative care).

3.2 Surgery

Surgery is the only potentially curative treatment option for cholangiocarcinoma. In order to be effective, it must completely remove the cancer, and this may imply the resection of some portions of the liver (partial hepatectomy).
The possibility to completely remove the neoplasm depends on its location: up to 70% for distal cancers, 15%-20% for proximal ones.
Although the results of blood tests and radiological information may help to establish the possibility of removing all cancerous areas, this can only be confirmed during actual surgery, when the abdomen can be directly explored.

3.2.1 What differentiates surgical procedures?

Choice of the type of surgery depends on the position of the cancer in the bile duct and on its extension. Common objective of all procedures is to completely remove the cancer and restore bile duct function.
Intrahepatic CCA represents about 20%-30% of all CCAs. It starts in the liver, so partial hepatectomy (removal of part of the liver) is necessary, together with the removal of nearby lymph nodes. The liver tissue will grow again and work normally after the operation. In rare cases, liver transplantation can be considered.
Perihilar CCA accounts for 60%-70% of all CCAs. It starts where the right and left hepatic ducts join, just outside the liver. Surgery in this case is more difficult and requires removal of part of the liver and of the bile ducts, gallbladder, and nearby lymph nodes, and sometimes of part of the pancreas and small bowel. The surgeon will reconnect the remaining bile ducts to the intestine. Liver transplantation can be considered.
Distal CCA is the less frequent form of CCA (10%-15%). It starts in the bile ducts near the pancreas and small bowel. It requires a pancreaticoduodenectomy (i.e., the resection of the bile ducts, part of the pancreas, and part of the small bowel). If the tumour cannot be completely resected (because it is too extensive or because of the presence of metastases), surgical interventions are indicated in order to relieve symptoms (palliative surgery).

3.2.2 Side effects

In order to guarantee radical removal of cancerous tissues, surgery may turn out to be extensive and destructive. Consequently, the operation can have serious complications.

3.3 Radiotherapy (RT)

Radiotherapy (i.e., the use of high-energy rays to destroy cancer cells) may be used after surgery, to reduce the chance of the cancer coming back (adjuvant radiotherapy), or during surgery, by delivering high doses of radiation directly to cancer cells.
Radiotherapy is useful in controlling inoperable cancers and relieving symptoms, but it seems not to contribute to the prolongation of survival.
The radiotherapy may be external or internal. Internal radiotherapy (the one used during surgery) is also called brachytherapy.
Given the rarity of this type of cancer, there are no large studies available, nor are there data about the possibility to consider RT as standard treatment.

3.3.1 Side effects

The most common side effects are feeling or being sick, diarrhoea, reddening of the skin and loss of body hair in the treatment area, tiredness. All of them generally disappear within a few weeks after the end of treatment.
In some cases, when large portions of the liver are exposed to high doses of radiation, liver function may be impaired.

3.4 Photo Dynamic Therapy (PDT)

Photo Dynamic Therapy is a new type of treatment (especially for skin tumours and precancerous lesions) based on a chemical reaction involving light (photochemical process), the goal of which is to kill cancerous cells.
This treatment can be used as a palliative for CCA, but only in specialized centres.

3.5 Chemotherapy

Chemotherapy implies the use of drugs capable of destroying cancerous cells. The type of drugs that can be used as chemotherapeutic agents are different and vary in the mechanisms of action and side effects. Normally, they are given in combination (polychemotherapy), and are administered orally, or, more commonly, intravenously.
Chemotherapy can be administered before surgery, in order to reduce the size of the neoplasm, facilitating its resection (neoadjuvant chemotherapy), or after surgery, with the aim to diminish the chances of recurrences and metastases (adjuvant chemotherapy).
As for radiotherapy, and for the same reasons (lack of large studies because of the rarity of this kind of cancer), no data are available that demonstrate the efficacy of chemotherapy for bile duct cancer. It is offered mainly as palliative treatment when surgery in not possible (because of cancer dimensions and/or because of the diffusion of metastases) in order to control cancer growth and relieve symptoms.

3.5.1 Chemotherapeutic drugs

The chemotherapeutic drugs that have demonstrated the highest efficacy in the treatment of CCA are 5-fluorouracil (5-FU), gemcitabine, cisplatin, anthracyclines, nitrosoureas, mitomycin C.

3.5.2 Side effects

The side effects of chemotherapy depend on the type of drugs used, their dose, and their combination. The most common are: nausea and vomit, diarrhoea and constipation, hair loss, infections, fatigue, decrease in the number of blood cells.

4. Stages of Cholangiocarcinoma

The stage of a tumour indicates its extension and its spread beyond its site of origin (metastases). It is important in order to choose the most appropriate treatment.
Intrahepatic, hilar and distal CCA are classified separately using the TNM system. See Tables 5, 6, and 7 in Professional area.

4.1 TNM staging

It is the most commonly used system, where:

  • T refers to the size or position of the primary tumour (where the cancer first starts in the body);
  • N refers to which lymph nodes are affected, if any;
  • M refers to metastatic disease (when the cancer has spread to other parts of the body).

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that a treatment will be successful. It reflects statistical data obtained from different studies that observe the progress of the disease in a high number of patients. Generally, it is referred to as the percentage of survival at 5 or 10 years since the start of treatment: this indicates the percentage of patients that are still alive after 5 or 10 years since the beginning of therapy, as demonstrated in large studies.
It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.
For CCA, prognosis depends on the following.

5.2 Prognosis of cholangiocarcinoma

The most important factor affecting the chance of survival is the stage of the disease at diagnosis. Unfortunately, many patients are diagnosed when the disease is at an advanced stage, so for them the prognosis is not favourable: only 15%-20% of these persons are eligible for surgery which, as already mentioned, is the only curative treatment option for CCA.
Survival at 5 years for inoperable patients is less than 5%: in other words, less than 5 patients out of 100 will be alive 5 years after diagnosis.
After a radical resection of an intrahepatic CCA, survival at 5 years varies from 8% to 47%.
For extrahepatic CCAs, survival at 5 years ranges from 15% to 42% for localized and resectable cancers, while it does not reach 1% when metastases are present.
Survival after 5 years from liver transplantation is estimated to be 20%.

6. What to do after treatment

6.1 General information

After completing treatment, the oncologist will plan a series of visits and additional tests to monitor the effects of treatment, make sure that cancer does not recur, and make an early diagnosis in case of recurrence.
The check-up plan is called follow-up and is at least 5 years long. If there is no recurrence during this time, it means that the risk for the patient of having a cancer is the same as for the rest of the population.

6.2 The follow-up of cholangiocarcinoma

Generally, the oncologist will plan a clinical examination every 3-4 months for the first two years, and every 6 months for the next 3 years. Together with clinical exams, blood tests aimed at checking liver function and tumour marker CA 19.9 levels should be considered.
Abdominal ultrasound and/or CT scans should be done periodically. MRI scans, PET, and X-rays should be limited to specific individual situations.

7. What to ask doctors

General questions
• What should I do if I feel anxious and cannot sleep?
• May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
• What leaflets, books, or websites could I read to learn more about duct bile cancer?
• Is there a patient association I could contact?
• Do you have special advice regarding nutrition?
• Does duct bile cancer run in families? Are my children at risk of getting bile duct cancer?
• Do I need psychological support?

Diagnosis and exams
• What tests are you going to do?
• What are you looking for?
• What should I do in preparation for a CT or MRI scan?
• How long will the exam take?
• Is it painful?
• Will I be asleep?
• Should someone be with me?
• Are CT or MRI dangerous because of radiation exposure?
• Is biopsy painful? Is it performed under general or local anaesthesia?
• Is cholangiography, percutaneous or retrograde, performed under general or local anaesthesia?
• How long will it take to confirm diagnosis?

Treatment
• Which centre in my country has the highest expertise in treating this disease?
• What type of treatment do I need?
• Is there any choice of treatments?
• What are the risks and benefits of the treatments?
• What are the side effects?
• How can I help to reduce the side effects?
• What signs should I recognize so that I can tell the doctor and ask if the approach needs to be changed?
• Is surgery performed under general or local anaesthesia? Will it be painful? What should I do before and after surgery?
• What are the possible side effects of chemotherapy? Will I lose my hair? Will I have nausea and vomiting?
• Will I have fertility problems because of the disease or treatment?
• Will treatment reduce my pain?
• During treatment should I take special precautions or change my habits?
• Is there any behaviour I could adopt to improve my prognosis?
• What late effects could the treatments have?
• What type of supportive therapy is suggested during the treatment?
• How will my treatment affect me?
• Will I ever get back to normal, or will I have some long-term effects?
• Will I need a special diet?
• Is there anything I shouldn’t eat?
• Will I be able to go back to work?