What is the significance of elevated Carbohydrate Antigen 19-9 (CA-19-9)?

From the Guidelines

Elevation of CA-19-9 is a concerning laboratory finding that warrants further investigation, as it may indicate cholangiocarcinoma or other hepatobiliary malignancies in patients with primary sclerosing cholangitis (PSC). The recommended approach includes comprehensive imaging with contrast-enhanced MRI or MRCP of the abdomen, focusing on the biliary tract and liver, as these modalities have higher sensitivity and specificity for detecting hepatobiliary malignancies compared to ultrasound or CT scan 1.

Key Considerations

• CA-19-9 is not specific for cancer and can be elevated in benign conditions such as cholangitis, cirrhosis, and other inflammatory conditions.
• About 5-10% of the population cannot produce CA-19-9 due to Lewis antigen negativity, resulting in false negatives.
• The degree of elevation may correlate with disease burden in malignancy, with higher levels (>1000 U/mL) more strongly associated with cancer.
• Serial measurements are more valuable than single readings, particularly for monitoring treatment response in confirmed malignancies.

Diagnostic Approach

• Combination of serum CA19-9 and imaging is recommended, as it improves sensitivity and specificity for detecting hepatobiliary malignancies 1.
• A cut-off value of 20 U/mL for CA19-9 is suggested, as it provides a balance between sensitivity and specificity, although the optimal cut-off value may vary depending on the individual patient's characteristics and the presence of genotypic variants of fucosyl-transferases 2 and 3 1.
• Endoscopic retrograde cholangiopancreatography (ERCP) may be necessary for further evaluation, particularly if a biliary stricture is suspected, as it allows for direct visualization and sampling of the biliary tract 1.

Management

• Patients with elevated CA-19-9 should be referred to gastroenterology or oncology specialists for appropriate management based on the underlying cause.
• Early detection of cholangiocarcinoma can lead to curative liver transplantation, and current European Association for the Study of the Liver clinical guidelines recommend that biliary dysplasia detected with brush cytology represents a possible indication for liver transplantation 1.

From the Research

Elevation of CA-19-9

• The elevation of CA-19-9 is widely recognized as a tumor marker primarily associated with pancreatic cancer 2.
• However, its elevation in benign pancreaticobiliary conditions complicates its diagnostic utility 2, 3.
• CA 19-9 is a sensitive marker for pancreatic, gastric, and hepatobiliary malignancies, but high levels can also indicate unresectable lesions and a poor prognosis 3.
• Benign conditions associated with elevation of CA 19-9 include disease of the hepatobiliary system, pneumonia, pleural effusion, renal failure, and SLE 3.
• CA 19-9 levels were significantly lower in benign than in malignant conditions 3.
• The clinical utility of CA 19-9 in pancreatic adenocarcinoma includes diagnostic and prognostic updates, with a combined sensitivity of 78.2% and specificity of 82.8% 4.
• CA 19-9 serum levels have a sensitivity and specificity of 79-81% and 82-90% respectively for the diagnosis of pancreatic cancer in symptomatic patients 5, 6.
• Pre-operative CA 19-9 serum levels provide useful prognostic information, with patients with normal levels (<37 U/mL) having a prolonged median survival compared to patients with elevated levels (>37 U/mL) 5, 6.
• Important limitations to CA 19-9 serum level evaluation in pancreatic cancer include poor sensitivity, false negative results in Lewis negative phenotype, and increased false positivity in the presence of obstructive jaundice 5, 6.

Causes of Elevation

• Choledocolithasis, cholangitis, and biliary manipulation can contribute to a transiently elevated CA 19-9 2.
• Obstructive jaundice can cause increased false positivity in CA 19-9 levels 5, 6.
• Benign conditions such as disease of the hepatobiliary system, pneumonia, pleural effusion, renal failure, and SLE can also cause elevation of CA 19-9 3.

Clinical Interpretation

• Clinicians must consider the entire clinical context when evaluating elevated CA 19-9 levels to avoid misdiagnosis and ensure appropriate patient management 2, 3.
• CA 19-9 serum levels should be interpreted in the light of the clinical presentation of the patient, and awareness of benign conditions that can be associated with increased levels of this marker is essential 3.