Introduction 

Cholangiocarcinoma, which is a cancer of the bile ducts, is an aggressive and malignant cancer with poor overall survival rates. It is a complex tumour that is challenging to diagnose and treat, largely because its early-stage symptoms are usually subtle and can be overlooked. Some of these symptoms include jaundice, abdominal pain and weight loss, which can also be mistaken for other conditions. Imaging tests and biopsies are usually conducted and are crucial for diagnosis, although in some cases, tumour masses are not clearly identified. As a result, the disease is frequently diagnosed at an advanced stage.¹

An ideal serum marker used as a diagnostic test would support early detection and lead to more effective management interventions. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are proteins that have been shown to be elevated in certain cancers and have been proposed as potential serum tumour markers for cholangiocarcinoma. They are glycoproteins that are expressed at higher levels on the surface of cancer cells. This article will introduce cholangiocarcinoma as well as explore the utility and limitations of CA 19-9 as a tumour marker for cholangiocarcinoma.^1,2

What is cholangiocarcinoma?

Cholangiocarcinomas are cancers of the bile ducts. Bile, a fluid made in the liver and stored in the gallbladder, plays a role in breaking down fats during digestion. Bile ducts are tubes that connect the liver, gallbladder and small intestine to transport bile when it's needed. Cholangiocarcinoma can be classified into intrahepatic cholangiocarcinoma, which originates from the bile ducts within the liver, and extrahepatic cholangiocarcinoma, which affects the bile ducts outside the liver. Approximately 80 per cent of cholangiocarcinomas are extrahepatic in nature. Imaging tests and biopsies are typically conducted, directing diagnosis.^1,3,4

Imaging tests

Some examples of common imaging tests that are used in finding cholangiocarcinoma include:^1,5

• Ultrasonography (ultrasound): This method is used for people with jaundice to test for bile duct dilation as well as to exclude other causes. Although it can detect masses present in the bile ducts, the effectiveness depends on several factors, including tumour location or the presence of liver cirrhosis 
• Computer tomography (CT): CT scans are used to both detect and see the growth of the cholangiocarcinoma. Although they can detect bile duct dilation and metastasis, the accuracy varies with different types of CT scans 
• Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreaticography (MRCP): MRI scans in combination with MRCP are particularly useful in detecting local tumour extension and have been successful; however, these methods lack sensitivity in some cases, which can contribute to a late diagnosis 

What is CA 19-9?

CA 19-9 is a mucin-type glycoprotein that is typically found at low levels in healthy people. In certain cases, especially in pancreatic cancers or cholangiocarcinomas, CA 19-9 levels can rise in the blood.^2,6

This glycoprotein itself is expressed on many epithelial cells. Cholangiocarcinoma arises from the epithelial cells lining the bile ducts; therefore, CA-19-9 levels are especially high due to its overexpression as well as the release of the protein from cancerous cells. It is important to note that approximately ten per cent of the population does not express CA 19-9 because of a genetic variation that lacks the enzyme required to produce the protein. Nevertheless, its production by ductal epithelial cells within the biliary system makes it a useful tool in diagnosing cholangiocarcinoma.^6,7,8

Utility of CA 19-9 in cholangiocarcinoma

Diagnostic utility

CA 19-9 has shown promise as a tumour marker for detecting cholangiocarcinoma, particularly when used in combination with imaging tests such as CT, MRI, and ultrasonography. As a serum marker, CA 19-9 levels can be easily measured through blood tests, and they are typically elevated in people with cholangiocarcinoma. 

Studies have shown a positive rate of CA 19-9 results ranging from 68 per cent to 97 per cent in bile duct cancers. A meta-analysis study found that a CA 19-9 level greater than 37 KU·L⁻¹ has shown a sensitivity of 77.14 per cent and an accuracy of 82.68 per cent for diagnosing cholangiocarcinoma. Another study calculated a diagnostic odds ratio, which combines sensitivity and specificity to test for accuracy, of 15.1. The high odds ratio shows that the marker is valuable in diagnosing cholangiocarcinoma.^1,2,7

Prognostic utility

Serum CA 19-9 levels have been shown to correlate with tumour burden and stage. Greater levels of CA 19-9 are typically indicative of more advanced disease, which negatively impacts overall survival outcomes. 

A study identified that people with cholangiocarcinoma that were unable to be removed by surgery had greater average CA 19-9 levels compared to those that were, with a sensitivity of 67.5 per cent versus 86.8 per cent, respectively. In addition, another study found a significant reduction in the concentration of CA 19-9 in people who had undergone a tumour resection operation compared to those who had not. This highlights the importance of CA 19-9 not only in predicting disease stage but also the resectability of the tumour.^2,5

Monitoring 

CA 19-9 has been shown to be useful in following the response or effectiveness of a treatment as well as detecting the risk of a person recurring. An increase in CA 19-9 levels following treatment could indicate that the person is relapsing, which allows for rapid interventions or adjustments to the treatment plan.^2,5

Limitations of CA 19-9 in cholangiocarcinoma

Lack of specificity 

CA 19-9 levels are not only elevated in cholangiocarcinoma but also in pancreatic cancer, colorectal cancer and gastric cancer. This overlap highlights the need to incorporate other diagnostic tests in combination with CA 19-9 measurement.⁵

CA 19-9 levels have also been shown to increase with benign inflammatory diseases such as acute cholangitis or bile stones. Choledocholithiasis, a condition where gallstones are present in the bile duct, can lead to obstruction of bile flow. It has been suggested that the inflammation of the epithelial cells lining the bile duct caused by choledocholithiasis can lead to more CA 19-9 being released from the epithelial cells. This leads to a higher concentration of CA 19-9 in the blood. In addition, the presence of liver cirrhosis or pancreatitis can also raise CA 19-9 levels.^2,5,6

It is important to note that measuring CA 19-9 alone cannot be used to diagnose cholangiocarcinoma, and a negative result cannot rule out the disease either. 

Negative results

Five to ten per cent of the population lacks the expression of CA 19-9 completely due to a genetic variation. This makes the test ineffective in these people, where they could develop cholangiocarcinoma without an increase in CA 19-9, even with a potential advanced disease stage. In some cases, tumours can also lose expression of CA 19-9, leading to false negative results.⁷

A study investigated the sensitivity and specificity of CA 19-9 in cholangiocarcinoma in different ethnicities. Although specificity was similar, the sensitivity of the test was lower in European countries compared to Asian and American populations. The reduced sensitivity means that the test is less effective at detecting disease and can lead to missed diagnoses. A higher rate of false negative results in certain populations can also delay treatment interventions, leading to impaired overall outcomes.⁷

Summary

Cholangiocarcinoma, or bile duct cancer, is an aggressive cancer with poor overall survival rates. Non-specific symptoms make diagnosis and treatment challenging, with most cases diagnosed at an advanced stage. A serum marker that can be measured through blood tests is ideal to support diagnosis and early detection. Carbohydrate antigen 19-9 (CA 19-9) is a glycoprotein that has been shown to be elevated in cholangiocarcinoma, making it a useful tool in diagnosis, prognosis and monitoring of both recurrence and response to treatment. CA 19-9 has shown promise in several studies as a tumour marker for cholangiocarcinoma, especially when used in combination with imaging tests. However, it is important to note that CA 19-9 is not specific to cholangiocarcinoma and can be elevated in other cancers or inflammatory conditions. In addition, the protein itself is also not expressed in five to ten per cent of the population. The sensitivity and specificity also vary between different ethnicities. Therefore, a combinatory approach, as well as further research into additional markers, is essential in improving the management of cholangiocarcinoma.