Carbohydrate Antigen 19-9

Carbohydrate antigen 19-9 (CA 19-9) is a sialylated Lewis-a blood group antigen carried on mucin. It is expressed by pancreatic and biliary duct epithelium, gastric and colonic mucosa and several other tissues. About 5 to 10% of the population are Lewis negative (Le a-b- genotype) and cannot make CA 19-9, so they have undetectable levels even with large tumours. It is measured in serum by immunoassay in U/mL (kU/L).

The test is mainly used to monitor response and detect recurrence in pancreatic cancer and, to a lesser extent, biliary, gastric and colorectal cancers. It is a prognostic marker before treatment. It is not a screening test and not a diagnostic test for pancreatic cancer, because it is raised in many benign diseases.

Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide, with a five year survival of about 10%. Most cases present with advanced disease, and only 15 to 20% are resectable at diagnosis. The test has sensitivity of 70 to 90% and specificity of 70 to 90% for symptomatic pancreatic cancer.

Indications. Baseline and follow up of pancreatic or biliary cancer, monitoring of response to chemotherapy, assessment of resectability and prognosis, and detection of recurrence after surgery. Supportive use in a patient with a pancreatic mass, weight loss, painless jaundice or new onset diabetes in older age.

Specimen. Serum. No fasting is needed. Stable for days at 2 to 8 °C. Consider the Lewis genotype if the value is undetectable in a patient with a proven tumour. Biliary obstruction must be relieved or considered before interpretation.

Reference range. Under 37 U/mL (under 37 kU/L) in most assays.

Pancreatic cancer.

• Preoperative CA 19-9 over 37 U/mL occurs in about 80 to 90% of symptomatic patients. Over 1000 U/mL indicates advanced or metastatic disease in most, and values over 100 U/mL suggest unresectable disease in many (a threshold for staging laparoscopy and neoadjuvant treatment in some centres).
• A postoperative value that falls to under 37 U/mL (half life about 1 to 2 days, normalisation by 4 to 8 weeks) predicts long survival, and a persistent raised value predicts early recurrence.
• On chemotherapy, a fall of at least 50% predicts better survival, and a rise predicts progression and precedes imaging by 2 to 6 months.
• A level that is normal before treatment in a Lewis positive patient cannot be used for monitoring, and imaging is used.

Biliary and other cancers. Cholangiocarcinoma (sensitivity 50 to 80%, with levels over 129 U/mL supporting malignancy in primary sclerosing cholangitis), gallbladder cancer, gastric cancer (about 25 to 50%), colorectal cancer (about 20 to 40%), ovarian mucinous tumours, and hepatocellular carcinoma. Raised values in pancreatic cyst fluid support mucinous cysts but not malignancy.

Benign causes of raised CA 19-9.

• Biliary: obstructive jaundice from any cause (stones, stricture, cholangitis; values commonly 100 to over 1000 U/mL), acute cholangitis, primary sclerosing cholangitis, and primary biliary cholangitis.
• Pancreatic: acute and chronic pancreatitis, pancreatic cysts, and cystic fibrosis.
• Hepatic: cirrhosis, hepatitis, and liver abscess.
• Other: diabetes, inflammatory bowel disease, thyroid disease, endometriosis, bronchiectasis and other lung diseases, ovarian cysts, and heavy smoking.

Lewis negative patients. About 5 to 10% (less in some populations, and varying with ancestry) make no CA 19-9, so a normal result in a patient with a pancreatic mass has no weight. A raised CEA or another marker may be informative.

Critical values and findings needing immediate action.

• CA 19-9 over 1000 U/mL with jaundice or abdominal mass: urgent imaging and referral. Drain biliary obstruction before reliance on values.
• A rising CA 19-9 after resection of pancreatic cancer.
• Raised CA 19-9 with fever, rigors and jaundice (cholangitis), which needs urgent biliary drainage.
• Weight loss, new diabetes or back pain with a raised value in an older adult.

Interferences and pitfalls.

• Biliary obstruction and cholangitis can raise CA 19-9 into the thousands without cancer, and the test is repeated after drainage.
• Not a screening test: positive predictive value in asymptomatic people is under 1%.
• Lewis negative status gives false negatives.
• Heterophile antibodies and human anti-mouse antibodies cause false positives, and biotin interferes with some assays.
• Different assays give different values, and the same method is used for serial testing.
• Normal results do not exclude small or early tumours.
• Smoking, diabetes and acute illness raise values modestly.

Special groups.

• Older adults with new onset diabetes and weight loss: CA 19-9 supports a pancreatic cause when imaging is suggestive.
• Primary sclerosing cholangitis: surveillance with CA 19-9 and imaging, since the cancer risk is high.
• Patients with hereditary pancreatic cancer risk (BRCA2, PALB2, CDKN2A, Peutz-Jeghers, hereditary pancreatitis): CA 19-9 is not sufficient for surveillance, and imaging is used.
• Children: rarely used.
• Regions: liver fluke infection (Opisthorchis, Clonorchis) raises cholangiocarcinoma risk, and CA 19-9 may be raised by infection.

Follow up tests. pancreatic phase CT, MRI and MRCP, endoscopic ultrasound with biopsy, CEA, bilirubin, ALP, GGT, liver function tests, lipase, glucose and HbA1c, Lewis phenotype or genotype, staging laparoscopy, tumour sequencing (BRCA, PALB2, KRAS, mismatch repair), and germline genetic testing.