What is carbohydrate antigen 199 (CA 19-9)?

What is Carbohydrate Antigen 19-9 (CA 19-9)?

CA 19-9 is a tumor-associated antigen that exists as an epitope of sialylated Lewis A blood group antigen, originally defined by a monoclonal antibody produced from murine spleen cells immunized with human colorectal cancer cell lines. 1

Biochemical Definition

• CA 19-9 is a cell surface glycoprotein complex, also known as sialyl Lewis A antigen, that is normally synthesized by pancreatic and biliary ductal cells, as well as gastric, colon, endometrial, and salivary epithelia 2, 3
• It is measured in serum using a radioimmunometric assay 1
• The antigen is present in small amounts in normal serum but can be dramatically overexpressed during neoplastic disease 2, 4

Critical Biological Limitation

• Approximately 5-10% of the population is genotypically Lewis antigen-negative (Lewis a-b-) and cannot produce CA 19-9, making testing completely ineffective in these individuals 5, 6, 2
• Lewis antigen status should be determined when CA 19-9 results are unexpectedly low or normal in the setting of suspected malignancy 6

Clinical Applications

Primary Use: Pancreatic Cancer Biomarker

• CA 19-9 is the most commonly used and best validated serum tumor marker for pancreatic cancer diagnosis in symptomatic patients and for monitoring therapy 2, 7
• It is elevated in up to 85% of patients with pancreatic adenocarcinoma 5, 6
• Sensitivity is approximately 79-81% and specificity is 82-90% for pancreatic cancer diagnosis in symptomatic patients 5

Other Malignancies

• CA 19-9 is elevated in cholangiocarcinoma (up to 85% of patients), colorectal cancer, hepatocellular carcinoma, ovarian cancer, and other upper gastrointestinal tract tumors 1, 6
• It is not tumor-specific and cannot discriminate between different malignancies 6

Important Benign Causes of Elevation

CA 19-9 can be falsely elevated in numerous benign conditions, which is a critical pitfall in interpretation:

• Biliary obstruction (any cause, including choledocholithiasis) causes false-positive elevations in 10-60% of cases because CA 19-9 levels correlate directly with bilirubin levels 6, 8
• Inflammatory hepatobiliary conditions including cholangitis, pancreatitis (acute, chronic, and autoimmune), and inflammatory bowel disease 1, 6
• Hepatic cysts and polycystic liver disease (up to 50% of patients) 6
• Severe hepatic injury from any cause 6
• Thyroid disease and other benign conditions 1

What CA 19-9 Should NOT Be Used For

Screening

• CA 19-9 is explicitly NOT recommended as a screening test for pancreatic cancer in asymptomatic individuals due to inadequate sensitivity, specificity, and poor positive predictive value (72.3%) 1, 5, 2

Determining Operability

• CA 19-9 testing alone is NOT recommended for determining operability or resectability of pancreatic cancer 1, 5
• Preoperative levels may correlate with outcomes, but cannot be used in isolation for surgical decision-making 1

Definitive Evidence of Recurrence

• CA 19-9 determinations by themselves cannot provide definitive evidence of disease recurrence without confirmation by imaging studies and/or biopsy 1, 5

Appropriate Clinical Use

Monitoring Treatment Response

• CA 19-9 can be measured at the start of treatment for locally advanced or metastatic disease and every 1-3 months during active treatment 1, 5
• Rising CA 19-9 levels may indicate progressive disease, but confirmation with imaging studies is mandatory 1, 5
• Serial normal-range CA 19-9 values can be useful for monitoring disease activity when baseline levels are normal 9

Prognostic Value

• Preoperative CA 19-9 ≥500 U/mL indicates worse prognosis after surgery 5, 8
• CA 19-9 >100 U/mL is associated with advanced disease, lower likelihood of resectability, and increased probability of occult metastases 5, 8
• Normal baseline CA 19-9 levels are associated with long-term survival 7

Critical Interpretation Pitfall: Biliary Obstruction

The single most important clinical pitfall is interpreting CA 19-9 in the presence of jaundice or biliary obstruction:

• Always relieve biliary obstruction FIRST and recheck CA 19-9 after complete biliary decompression 6, 8
• Persistent elevation after decompression strongly suggests malignancy and mandates aggressive investigation 6, 8
• Normalization of CA 19-9 after decompression indicates a benign etiology 6

Emerging Roles Beyond Biomarker

• CA 19-9 functions not only as a biomarker but also as a promoter of cancer progression by glycosylating proteins, binding to E-selectin, strengthening angiogenesis, and mediating immunological responses 7, 4
• It represents an attractive therapeutic target through therapeutic antibodies, vaccines, CA 19-9-guided nanoparticles, and inhibition of CA 19-9 biosynthesis 7, 4