A General Guide To Hepatobiliary Cancers – Know Your Liver, Bile Duct & Gallbladder
Table of Contents
- 1. What is hepatobiliary cancer?
- 2. Liver cancer
- 3. Bile duct cancer
- 4. Gallbladder cancer
- 5. Preventing hepatobiliary cancers
- 6. Takeaway message
Hepatobiliary cancers refer to cancers that start from an organ of the hepatobiliary system. Since the hepatobiliary system consists of the liver, the gallbladder and the bile duct, hepatobiliary cancers include liver cancer, gallbladder cancer and bile duct cancer.
By far, liver cancer is the most common among cancers affecting the hepatobiliary tract. Bile duct and gallbladder cancers, despite having a much lower incidence rate compared to liver cancer, are no less dangerous. For instance, the 5-year survival rate of intrahepatic bile duct cancer is barely 25% for cases detected early. More often than not, hepatobiliary cancers are discovered at late stages when treatment outcomes are compromised.
In this article, we will discuss what causes delayed diagnosis of hepatobiliary cancers. Similar to other cancer guides we have published, their symptoms, causes, diagnoses, and treatments are also covered for you to have a good general understanding of the diseases.
1. What is hepatobiliary cancer?
To understand hepatobiliary cancer, let us first get familiarised with the hepatobiliary system. Anatomically speaking, the hepatobiliary system describes the association of three organs working together to digest fat from the food we eat, namely the liver, the gallbladder and the bile duct.
The liver produces a fluid called bile, which aids in breaking down and digesting fatty food. Unused bile secreted by the liver moves through the bile duct into the gallbladder for storage. When bile is needed – which is when we eat – the gallbladder releases it through the common bile duct into the small intestine to help with lipid digestion.
Hepatobiliary cancer occurs when the cells in any part of the hepatobiliary system go rogue and multiply in an uncontrolled manner. If this process starts from the liver, cancer is known as liver cancer, the most common form of which is known as Hepatocellular Carcinoma (HCC). If hepatobiliary cancer develops from the bile duct, it is referred to as bile duct cancer or cholangiocarcinoma (CCA). When cancer breaks out from the gallbladder, it is gallbladder cancer or gallbladder carcinoma. Cancers of the bile duct and gallbladder are referred to as biliary cancers.
Note that when oncologists mention hepatobiliary cancer, they refer to primary cancer, which is to say cancer that originates from the hepa system. Cancer that starts elsewhere and spreads to the hepa organs are not considered hepatobiliary cancer.
2. Liver cancer
Liver cancer is the most common hepatobiliary cancer and one of the top fatal cancers worldwide. Despite progress in fighting it at national level, it remains the third and fourth cause of death in men and women with cancer in Singapore respectively. As such, we posted a general guide to liver cancer in Singapore earlier, detailing its causes, diagnosis, treatment and preventive measures. In this article, we will focus on the other 2 hepatobiliary cancer affecting the bile duct and gallbladder.
3. Bile duct cancer
Bile duct cancer is the second most common hepatobiliary cancer after HCC. A more formal name for this cancer is cholangiocarcinoma (CCA).
The bile duct performs the job of transporting bile from the liver to the gallbladder and to the duodenum (i.e., the first section of the small intestine). It is made up of a network of tubes, divided into:
- Intrahepatic bile ducts refer to part of the tube network that carries bile inside the liver.
- Extrahepatic bile ducts refer to the tubes that transport bile outside the liver, i.e., from the liver to the gallbladder and from the gallbladder through the pancreas to the small intestine. They consist of the common hepatic duct and the common bile duct, which are also known as perihilar region and distal region of the bile duct respectively.
Types of bile duct cancer
Based on location of the cancer on the bile duct anatomy, there are two types of cholangiocarcinoma:
Intrahepatic bile duct cancer – As the name suggests, this form of cancer occurs in the intrahepatic section of the bile duct inside the liver. Compared to extrahepatic bile duct cancers, this type is relatively rare. Oncologists refer to it as intrahepatic cholangiocarcinoma.
Extrahepatic bile duct cancer – This form of cancer starts from the extrahepatic bile ducts and further categorised into two more subtypes:
- Perihilar bile duct cancer – This cancer forms in the common hepatic duct area. You may hear your doctor referring to this cancer as a Klatskin tumour.
- Distal bile duct cancer – This type of extrahepatic bile duct cancer occurs at the distal parts of the common bile duct. It is also called distal extrahepatic cholangiocarcinoma.
Causes and risk factors of bile duct cancer
We know that cancer arises from gene mutations, but the exact causes of such mutations remain unclear. However, researchers have been able to pinpoint common risk factors that increase an individual’s chance of developing bile duct cancer. They include:
- Being over the age of 65
- Having concurrent medical conditions along the gastrointestinal tract, such as ulcerative colitis, liver flukes, bile duct stones (gallstones), liver cirrhosis, and abnormal bile ducts
Signs & symptoms of bile duct cancer
Bile duct cancer often develops without clear symptoms in the early stages. One reason is because of its location deep inside the body and its relatively small size. Tumour markers that have been linked to cholangiocarcinoma such as CEA (Carcinoembryonic Antigen) and CA 19-9 are not specific to bile duct cancer either. Thus, regular screening tests might not be able to catch bile duct cancer early.
In most cases, the signs and symptoms of bile duct cancer only manifest when cancer has reached advanced stages. But even at these stages, the signs and symptoms mimic any other condition that affects the liver or gallbladder, creating further diagnosis challenges for the doctors.
Nevertheless, reach out to your doctor if you notice any of the following symptoms:
- Jaundice or yellowing of the skin and eyes
- Abdominal pain
- Clay-colored stools
- Dark urine
- Digestive symptoms such as nausea, vomiting
- Fever
- Itchy skin
- Unexplained and rapid weight loss
Diagnosis & staging of bile duct cancer
Diagnosis of bile duct cancer follows the standard cancer diagnosis steps. First, the doctor or specialist will take your medical history to identify your symptoms, triggering factors, concurrent medical conditions, history of surgery, and others. After that, the doctor will examine your abdomen using light pressure to locate the pain and look for any lumps. For bile duct cancer, the clinical examination is often without any findings.
More diagnosis steps will follow to rule out other causes and confirm bile duct cancer, including:
- A complete blood count (CBC) with liver function tests
- Imaging scans, such as CT scans, MRIs, and ultrasound
- Ultrasound-guided endoscopy to take a closer look at the tumour
- Using a special endoscope to collect a biopsy, which is sent to the pathology lab. Once there, the pathologist will identify any unique features that indicate bile duct cancer and its stage. This is the gold standard diagnostic tool for cancer.
Note that your doctor may not necessarily order all of these tests, depending on your presenting symptoms and findings along the way. In the event bile duct cancer is confirmed, the oncologist will also be able to tell the type and stage of bile duct cancer. Staging definitions differ slightly by the type of cholangiocarcinoma. Generally speaking, the stages of bile duct cancer include:
- Stage 0 (Carcinoma in situ) – The malignant cells are present in the innermost layer of the bile duct (the mucosa)
- Stage 1 – The tumour has spread to the muscular layer of the bile duct or has grown to the size of 5cm.
- Stage 2 – The cancer has spread to nearby connective tissues or a few nearby lymph nodes.
- Stage 3 – The cancer has invaded nearby organs. The liver is commonly the first organ to be affected.
- Stage 4 – The cancer has metastasized to distant organs.
For treatment purposes, oncologists may refer to stage 0,1,2 and some cases in stage 3 as resectable, which is to say the tumours can be removed in its entirety by surgery. More advanced tumours in stage 3 and stage 4 which are impossible to be removed completely by surgery are referred to as unresectable.
Treatment of bile duct cancer
Recommended methods of treatment for bile duct cancer depend on a number of individual factors:
- The size of the tumour and type of bile duct cancer
- The location of the tumour within the bile duct
- The extent the tumour has spread to other tissues or organs
- Your general health to assess whether you can handle certain therapies
The most common options to choose from include surgery, chemotherapy and chemoradiation therapy.
Surgery
If test results show that bile duct cancer is in early stages and has not yet spread beyond the ducts, surgery is the best course of action to get rid of the cancer.
During the procedure, your surgeon will remove parts of the bile duct or its entirety. Nearby lymph nodes and organs may also get surgically removed. The purpose of this step is to prevent cancer recurrence.
Chemotherapy
This treatment uses cytotoxic medicine to kill rapidly growing cells which is how cancer cells typically behave. The indications to use chemotherapy for the treatment of bile duct cancer include:
- Post-surgery to reduce the chances of relapses and get rid of the remaining cancer cells that surgery may miss. This is known as adjuvant therapy.
- To address small-sized tumours
- To improve the patient’s symptoms after getting diagnosed with advanced bile duct cancer (palliative therapy)
Radiotherapy
Radiation therapy uses high-energy beams to kill cancer cells. However, the location of the bile duct and its entanglement with the liver, gallbladder and intestine makes targeting by traditional radiotherapy highly challenging. Minor body movements during breathing or digestion can make the bile ducts move, causing radiotherapy to miss its target.
Of late, advanced techniques in radiation therapy such as intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT) have improved precision and effectiveness. In the management of bile duct cancer, doctors may also recommend using radiotherapy in combination with chemotherapy after the surgery to better ensure that the cancer does not come up. This is known as chemoradiotherapy.
Sometimes, it is helpful to use radiotherapy or chemoradiotherapy to improve the patient’s symptoms as part of palliative treatment in advanced cases. Learn more about palliative care for cancer patients in our dedicated article here.
Targeted therapy for bile duct cancer
Targeted drugs are sometimes given to patients when standard chemotherapy drugs don’t work. The approach is to target the changes in proteins on cells that fuel cancer growth. As such, targeted therapy does not affect healthy cells, unless they share similar proteins or targets. However, it requires that the patients have a certain gene mutation that matches the target protein – a condition not all patients meet.
In bile duct cancer treatment, researchers have identified 2 types of proteins – FGFR2 and IDH1, on which targeted drugs have been successfully developed.
FGFR2 inhibitors
The FGFR (fibroblast growth factor receptor) gene family plays an important role in the regulation of cell division and growth. In a number of people with bile duct cancer, specific changes in the FGFR2 gene cause cells to multiply uncontrollably, advancing cancer. Targeted therapy aims to ‘inhibit’ or control the FGFR2 protein in these patients, keeping bile duct cancer from growing and spreading. Approved FGFR2 inhibitors include Pemigatinib (Pemazyre®), Infigratinib (Truseltiq®), and Futibatinib (Lytgobi®).
The indication of these drugs is for advanced bile duct cancers that have spread and cannot be removed by surgery. Patients will need to be tested for a certain type of abnormal FGFR2 mutation to be candidates for these targeted drugs. Targeted drugs are often in the form of pills or capsules that you can take orally at home.
Some of the side effects of FGFR2 inhibitors include vision problems, kidney problems, hyperphosphatemia, hair loss, dry skin, digestive distress, fatigue, loss of appetite, joint and back pain, and mouth sores. You are recommended to inform your doctor of existing eye, liver, kidney issues if you are prescribed these drugs.
IDH1 inhibitor
The IDH1 gene makes a protein that catalyses the breakdown of fat and supports cell protection. In a number of people with bile duct cancer, the protein made by the mutated IDH1 gene is abnormal and fails to do its job. IDH1 inhibitor seeks to control bile duct cancer by blocking this abnormal protein.
One of the IDH1 inhibitors is ivosidenib (Tibsovo®). It is indicated for advanced bile duct cancer that has spread and been previously treated. Similar to other targeted drugs, patients need to have a specific type of abnormal type of abnormal IDH1 mutation for the drug to work.
Reported side effects include fatigue, digestion distress, anaemia, loss of appetite, rash cough, low red blood cell counts (anaemia), rash, heart issues, nervous system problems, and changes in liver function. It is best to let your oncologist know if you have existing conditions related to the heart, nervous system, liver or kidney if you are a candidate for this drug.
Prognosis of bile duct cancer
The 5-year survival rate for intrahepatic bile duct cancer is very low. Even an early diagnosis of this disease will not give the patient more than a 25% survival rate. When the cancer spreads to nearby lymph nodes, the survival rate drops to 8%. Sadly, metastatic bile duct cancer has a survival rate of only 2%.
For extrahepatic bile duct cancers, things are slightly better. For instance, the 5-year survival rate of bile duct cancer with regional lymph nodes is 16%.
Do note that these statistics do not take into account individual factors such as age, responses to treatment and health status. Patients are recommended to discuss with their oncologist for a better understanding of their own prognosis.
4. Gallbladder cancer
Gallbladder cancer is a malignant tumour that develops within the gallbladder – the organ responsible for storing bile.
The gallbladder has four layers:
- The inner layer (mucosal layer)
- The muscle layer
- The connective tissue layer
- The outer layer (serosal layer)
Gallbladder cancer typically starts at the innermost layer, which is the mucosa. After that, it travels outward until it breaches the serosal layer and spreads to the nearby tissues. In clinical practice, a large number of gallbladder cancers get discovered after the surgical removal of the gallbladder, often due to gallstones.
Types of gallbladder cancer
Measuring 7-10 centimetres in length and 4 centimetres in diameter on average, the gallbladder houses various cell types. Cancer stemming from each type of cell gives rise to a different type of gallbladder cancer, with its unique features and often drastically different outcomes.
Here are the known cancers of the gallbladder:
- Adenocarcinoma – gallbladder cancer that develops from the gland cells of the gallbladder. Over 90% of gallbladder carcinoma falls into this category.
- Squamous cell cancer – gallbladder cancer that originates from the cells that line the inside of the gallbladder
- Adenosquamous cancer – gallbladder cancer that involves both the gland cells and squamous cells (i.e., a combination of adenocarcinoma and squamous cell carcinoma of gallbladder)
- Small cell cancer – although very rare, this type of gallbladder cancer is highly aggressive
- Sarcoma – in rare cases, cancer develops from the muscle layer of the gallbladder. This is known as sarcomatoid carcinoma of the gallbladder or gallbladder carcinosarcoma. Sarcoma is a separate cancer type, which we wrote about in our guide to sarcoma, lumps and bumps.
- Neuroendocrine tumour – this type of cancer starts from the neuroendocrine cells in the gallbladder and is considered an aggressive type. Learn more about neuroendocrine tumour (NET) in details here.
- Lymphoma and melanoma – considered extremely rare, this type of gallbladder cancer behave differently from the other types. You can learn more about them from our articles on lymphoma and melanoma.
Causes and risk factors of gallbladder cancer
As with other cancers, the definitive causes of gallbladder cancer are still being studied by scientists. However, we know that people with the following risk factors have an increased chance of getting gallbladder cancer:
- Having gallstone or having had gallstone in the past
- Having bacterial infections that can affect the gallbladder, commonly typhoid and Helicobacter pylori infection
- Having polyps in the gallbladder
- Having conditions that affect the bile duct, including cysts in the common bile duct or primary sclerosing cholangitis (or PSC – a chronic liver disease that causes inflammation and scarring of the bile duct), or abnormalities in the bile duct
- Being over the age of 65
- Other factors that have been linked to gallbladder cancer include family history of the disease, obesity, long-term exposure to carcinogens such as chemicals from rubber industries
Signs & symptoms of gallbladder cancer
Similar to other hepatobiliary cancers, the detection of gallbladder cancer is challenging due to the absence of symptoms that indicate a malfunction in gallbladder. Moreover, most symptoms of gallbladder cancer mimic benign conditions, such as gallstones.
With that said, here are some of the classic symptoms caused by gallbladder cancer:
- Jaundice – Yellowing of the skin and eyes
- Digestive symptoms such as nausea, vomiting, bloating
- Abdominal lumps
- Pain at or near the gallbladder – this is known as epigastric pain which typically occurs in the upper area of the abdomen under the rib cage
- Fever
Diagnosis & staging of gallbladder cancer
The diagnosis of gallbladder cancer involves taking your medical history and conducting a full clinical examination. If you visit a GP and the doctor suspects cancer, you will be referred to a specialist or oncologist for more tests to confirm it. These tests include:
- Blood tests: measuring complete blood count, tumour markers such as carcinoembryonic antigen (CEA), etc
- Liver function tests
- CT-scan
- MRI scan
- Endoscopic retrograde cholangiopancreatography (ERCP) to look closely at the gastrointestinal tract
- Laparoscopy to perform a biopsy
- Chest X-rays to detect the spread of cancer
Confirmation of gallbladder carcinoma will also come with the type and stage of the cancer. Without knowing the type and stage, it is difficult to treat gallbladder cancer.
Here are the 4 stages of gallbladder cancer:
- Stage 0 (Carcinoma in situ) – The tumour remains within the mucosal layer of the gallbladder.
- Stage 1 – The cancer has reached the muscular layer.
- Stage 2 – The cancer has reached the connective tissues.
- Stage 3 – The cancer is affecting nearby organs, most commonly the pancreas. bile ducts and liver.
- Stage 4 (metastasis) – The cancer has spread to distant organs.
Treatment of gallbladder cancer
Surgery
The procedure to remove the gallbladder with surgery is known as a cholecystectomy. Aside from the gallbladder itself, the surgeon will also remove nearby lymph nodes and tissues. This is known as the safety margin. This option is generally indicated for people with early stage cancer when the tumour has not spread.
After the surgery, bile will drip directly to the intestine without being stored in the gallbladder. This may make it difficult for the body to digest fatty foods and cause symptoms such as bloating, gas pain, diarrhoea. However, it is manageable with dietary adjustment.
Chemotherapy
Chemotherapy uses medicines that kill all rapidly growing cells, including cancer cells. When treating gallbladder cancer, your doctor may prescribe one or more of the following agents:
- 5-fluorouracil (5-FU)
- Capecitabine (Xeloda®)
- Gemcitabine (Gemzar®)
- Cisplatin (Platinol®)
- Oxaliplatin (Eloxatin®)
In most cases, chemotherapy is recommended as an adjuvant therapy or palliative therapy. With the adjuvant approach, it is administered after surgery to ensure all cancer cells are eliminated and cancer does not come back. With the palliative approach, the objective is to manage pain and other symptoms, thereby improving the quality of life for patients with advanced cancer.
Since chemotherapy drugs affect healthy fast growing cells as well, they may lead to hair loss, sores and blisters in the mouth, bleeding, bruising, infections, anorexia (i.e., loss of appetite), nausea, diarrhoea, and vomiting. Do ask your oncologist for recommendations to manage these side effects better.
Radiation
Radiotherapy to treat gallbladder cancer achieves better results with advanced techniques such as stereotactic body radiation therapy (SBRT), similar to the case of bile duct cancer. In reality, it is often used in advanced gallbladder cancer as a palliative treatment. The specific targeting of radiation therapy reduces the risk of damaging the adjacent organs and side effects. As such, oncologists may recommend it to reduce the size of large tumours that cause blockage or pain.
Prognosis of gallbladder cancer
The challenges in detecting gallbladder cancer early has a significant impact on its prognosis. According to statistics, almost 45% of cases are discovered after the cancer is in stage 3 while 42% of cases get diagnosed after the cancer is in stage 4.
Similar to other tumours affecting the hepatobiliary system, the very late diagnosis of gallbladder cancer results in poor survival rate. Documented median survival for advanced stage gallbladder cancer is approximately a year.
5. Preventing hepatobiliary cancers
Though we do not have a surefire way to prevent hepatobiliary cancer, managing the identified modifiable risk factors can provide some level of protection against getting it. This includes taking vaccination against typhoid if you have not gotten it as a child, treating chronic Helicobacter pylori infection, treating and eliminating polyps and cysts in the bile duct and gallbladder early. Additionally, maintaining good dietary habits, a healthy weight and living an active lifestyle is believed to help mitigate the risk of cancer and many other health issues.
If you have a family history of hepatobiliary cancer, consult an oncologist for suitable screening tests. Though we do have a sensitive screening method for this cancer, your doctor can advise you of measures to detect early if any cancerous process is taking place in the hepatobiliary system. As we discussed above, delayed discovery of the disease is one of the main reasons for the poor prognosis of hepatobiliary cancer.
6. Takeaway message
Hepatobiliary cancers are dangerous diseases with a relatively low survival rate. Due to the delayed discovery of these cancers, the outcome is typically poor. However, new and advanced treatment methods are constantly being developed, helping patients manage the disease more effectively and achieve better quality of life. At an individual level, having a knowledge of these cancers and managing your own risk factors will provide you with some protection, which we wish to achieve with this article.
