Carcinoembryonic Antigen

Carcinoembryonic antigen (CEA, CEACAM5) is a 180 kDa glycoprotein of the cell surface that is expressed in foetal gut and, at low levels, in adult colonic mucosa. It is shed into the blood by colorectal adenocarcinomas and several other epithelial cancers. It is measured by immunoassay in serum, reported in microg/L (ng/mL). It is not a screening test, because it is raised in many benign conditions and is normal in many early cancers.

The main use is monitoring of colorectal cancer: a preoperative baseline for prognosis, follow up after resection to detect recurrence, and response to treatment in metastatic disease. It also helps in medullary thyroid carcinoma (with calcitonin), lung and breast cancer, and in pleural and other fluid analysis.

Colorectal cancer is the third commonest cancer worldwide, with about 1.9 million cases and 900 000 deaths each year. About half of patients develop recurrence, most often in the liver, and 80% of recurrences occur within 3 years. Smoking raises CEA modestly, so smokers have wider reference limits.

Indications. Baseline before surgery for colorectal cancer, surveillance after curative resection (every 3 to 6 months for 2 to 3 years, then every 6 to 12 months to 5 years), monitoring of chemotherapy in metastatic disease, medullary thyroid carcinoma, suspected recurrence with symptoms or imaging findings, and assessment of unknown primary cancer.

Specimen. Serum or heparin plasma. No fasting is needed. Stable for days at 2 to 8 °C. Record smoking status. The same assay and laboratory are used for serial results.

Reference range. Non-smokers: under 3.0 microg/L (some assays under 5.0). Smokers: under 5.0 to 10 microg/L. Values over these limits are not abnormal in themselves unless they rise on serial testing.

Interpretation.

• Preoperative CEA over 5 microg/L in colorectal cancer predicts poorer prognosis independent of stage. Failure to normalise within 4 to 6 weeks of surgery (half life 3 to 7 days) suggests residual disease.
• After curative resection, a rise in 2 consecutive samples over the baseline (a sustained increase of 30 to 50% or an absolute rise over 5 microg/L) is an early sign of recurrence with a lead time of 3 to 6 months. It prompts CT, colonoscopy and PET-CT.
• In metastatic disease, a fall of 50% or more supports response, and a continued rise signals progression. A transient rise in the first weeks of chemotherapy (flare) can occur and is not progression.
• The sensitivity of CEA for early (stage I) colorectal cancer is 20 to 30%, and for stage IV it exceeds 80%. Its sensitivity for recurrence is 60 to 80%, and specificity is 80 to 90%.

Causes of raised CEA.

• Malignant: colorectal, gastric, pancreatic, lung (adenocarcinoma and small cell), breast, ovarian (mucinous), medullary thyroid, cervical, bladder and head and neck cancers.
• Benign: smoking, inflammatory bowel disease, diverticulitis, peptic ulcer, pancreatitis, cirrhosis and hepatitis, cholestasis, chronic obstructive pulmonary disease, pneumonia, hypothyroidism, renal failure, benign breast disease, and fibrocystic conditions.
• Older age and diabetes also contribute.

Body fluids. Pleural fluid CEA over 10 microg/L, or a pleural to serum ratio over 1, supports malignant effusion (sensitivity about 50 to 60%, specificity 90 to 95%). Cyst fluid CEA over 192 microg/L supports a mucinous pancreatic cyst, but does not distinguish malignant from benign mucinous cysts.

Medullary thyroid carcinoma. CEA with calcitonin gives prognosis, and a doubling time under 2 years indicates aggressive disease. Rapidly rising CEA with stable calcitonin suggests dedifferentiation.

Critical values and findings needing immediate action.

• A rising CEA after curative surgery for colorectal cancer, with new symptoms (weight loss, bleeding, liver pain, jaundice).
• A very high CEA (over 100 microg/L) with a mass or liver lesions.
• Rising CEA during chemotherapy beyond the early flare period.
• Raised CEA with unexplained weight loss, a pleural effusion or lymphadenopathy of unknown origin.

Interferences and pitfalls.

• CEA is not a screening test. A raised value in an asymptomatic person usually has a benign cause.
• Assays vary in range and cannot be interchanged, and a change of method needs a new baseline.
• Heterophile antibodies and human anti-mouse antibodies cause false elevations, and biotin interferes with some assays.
• Smoking raises values by 1 to 3 microg/L.
• Hepatic or renal dysfunction and inflammatory disease cause chronic modest elevation.
• A normal CEA does not exclude recurrence, and about 30% of colorectal cancers do not secrete it. A different marker or imaging is used.
• A flare after chemotherapy or radiotherapy is a transient rise.
• The hook effect can give a falsely low result in very high concentrations.

Special groups.

• Smokers and older adults: higher reference limits.
• Pregnancy: no major change.
• Children: reference limits are similar to adults, and the test has little use except in medullary thyroid carcinoma syndromes.
• Patients with inflammatory bowel disease: baseline values are higher, and trend matters.
• Regions: late presentation with advanced colorectal cancer is common, and the test mainly serves monitoring.

Follow up tests. Repeat CEA in 4 to 6 weeks, colonoscopy, CT of chest, abdomen and pelvis, PET-CT, liver MRI, CA 19-9, calcitonin, mismatch repair and RAS/BRAF testing in tumour tissue, liver function tests, full blood count, ferritin, faecal immunochemical test, and cytology or histology of fluid or tissue.