Tumour Markers

Classification

Major Serum Tumour Markers

1. Alpha-Fetoprotein (AFP)

• A glycoprotein (~70 kDa) with ~4% carbohydrate; considerable homology with albumin.
• Normally expressed by embryonic hepatocytes and fetal yolk sac cells; production falls sharply after birth.
• Primary uses: Diagnosis and monitoring of hepatocellular carcinoma (HCC), hepatoblastoma, and germ cell tumours (yolk sac tumour, embryonal carcinoma of testis/ovary). Prognosis of germ cell tumours.
• Also raised in: Gastric, colorectal, biliary, pancreatic, and lung cancers; non-malignantly in liver regeneration and pregnancy.
• AFP is neither sensitive nor specific enough to diagnose any particular tumour type alone. - Robbins & Kumar Basic Pathology

2. Carcinoembryonic Antigen (CEA)

• Family of glycoproteins, 45-60% carbohydrate, ~180 kDa.
• Primary use: Monitoring colorectal adenocarcinoma - especially post-surgical follow-up to detect liver metastases and asymptomatic recurrence. Inclusion of CEA in intensive follow-up after curative surgery has been shown to improve overall survival.
• Also raised in: Breast, gastric, lung, mesothelioma, oesophageal, and pancreatic cancers.
• Non-malignant causes of elevation: Colitis, diverticulitis, jaundice, irritable bowel syndrome, chronic liver disease, chronic renal failure. - Tietz Textbook of Laboratory Medicine
• Not recommended as a diagnostic or screening test for colorectal cancer; preoperative levels aid staging and prognosis. - Yamada's Textbook of Gastroenterology

3. Cancer Antigen 125 (CA125)

• A mucin (~200 kDa) identified by monoclonal antibodies OC125 and M11.
• Primary use: Monitoring ovarian carcinoma; required for calculating the "Risk of Malignancy Index" (RMI).
• Also raised in: Breast, endometrial, cervical, peritoneal, uterine, lung, pancreatic, and hepatocellular cancers; non-Hodgkin lymphoma.
• Highly non-specific - elevated in endometriosis, menstruation, pregnancy, pericarditis, ascites, congestive heart failure, pancreatitis, chronic liver disease, and many other benign conditions.

4. Cancer Antigen 19-9 (CA19-9)

• Primary use: Pancreatic cancer (typical presentation: progressive obstructive jaundice with profound weight loss).
• Also raised in: Colorectal, gastric, hepatocellular, oesophageal, and ovarian cancers.
• Non-malignant elevation: Acute cholangitis, cholestasis, acute/chronic pancreatitis, diabetes.

5. Cancer Antigen 15-3 (CA15-3) / CA27.29

• Primary use: Monitoring breast cancer.
• Non-malignant elevation: Acute hepatitis, chronic liver disease, chronic renal failure, dermatologic conditions, colitis.

6. Human Chorionic Gonadotropin (hCG / beta-hCG)

• Glycoprotein hormone with alpha and beta subunits (~36 kDa); the beta-subunit is cancer-specific.
• Primary uses: Diagnosis, prognosis, and monitoring of germ cell tumours (testicular, ovarian) and gestational trophoblastic neoplasia (choriocarcinoma, hydatidiform mole). One of the best examples of successful screening - for gestational trophoblastic neoplasia.
• Non-malignant elevation: Pregnancy, menopause.

7. Prostate-Specific Antigen (PSA)

• A glycoprotein produced by prostatic epithelial cells.
• Primary uses: Risk stratification at diagnosis of prostate cancer; monitoring response to treatment; detecting recurrence.
• PSA is not significantly altered by digital rectal examination (DRE), but is significantly affected by UTI - takes 6 weeks to return to baseline after an infection is treated.
• Artificially lowered (up to 2x) by 5-alpha-reductase inhibitors (finasteride, dutasteride). Also affected by aspirin, statins, and thiazide diuretics.
• Non-malignant elevation: BPH, prostatitis.
• PSA derivatives improve specificity: free PSA (fPSA), complexed PSA (cPSA), free/total PSA ratio (f/tPSA), PSA density (PSAD = tPSA / prostate volume), PSA velocity (>0.75 ng/mL/year is suspicious), and PSA doubling time.
• PSA screening in asymptomatic men remains controversial; not routinely performed in the UK. - Bailey and Love's Surgery, 28th Ed.

8. Testicular Markers Panel: AFP + beta-hCG + LDH

• The three markers routinely used for testicular cancer are AFP, beta-hCG, and LDH (lactate dehydrogenase).
• They help predict histological subtype, confirm treatment success, detect recurrence, and stratify prognosis using the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. - Bailey and Love's Surgery, 28th Ed.

9. Paraproteins (M protein / Bence-Jones protein)

• Primary use: Multiple myeloma (and other plasma cell dyscrasias).
• Measured in both serum and urine (Bence-Jones protein = urine light chains).
• Clinical context: anaemia, back pain, osteolytic lesions, raised ESR, spontaneous fractures, recurrent infections.

10. Lactate Dehydrogenase (LDH)

• A non-specific enzyme marker; elevation correlates with high tumour burden.
• Used in staging and monitoring lymphomas, testicular cancer, melanoma, and other malignancies.

11. Alkaline Phosphatase (ALP)

• Raised activity associated with presence of liver and/or bone metastases.

12. Neuron-Specific Enolase (NSE)

• Used for small cell lung cancer (SCLC) and neuroendocrine tumours.

13. Calcitonin

• Marker for medullary thyroid carcinoma; accelerating doubling time indicates clinical progression.

Tissue / Receptor Markers (used for targeted therapy)

Non-Malignant Causes of Elevated Tumour Markers (key examples)

Clinical Uses (Summary)

1. Screening - Limited; only hCG for gestational trophoblastic neoplasia is a near-ideal example. PSA screening is controversial.
2. Diagnosis - Rarely definitive on their own; contribute to risk stratification alongside imaging (e.g., AFP + ultrasound in HCC).
3. Staging / Prognosis - IGCCCG classification for testicular cancer; pre-op CEA levels in colorectal cancer.
4. Monitoring treatment response - Serial measurements are more informative than single values. Trends should be displayed graphically.
5. Detecting recurrence - CEA for colorectal cancer follow-up; PSA for prostate cancer post-treatment; AFP/hCG for germ cell tumours.
6. Identifying cancer of unknown primary - PSA (in men with bone metastases), AFP, CEA, CA19-9, CA15-3 can narrow the primary site.

Important Caveats

• A single tumour marker result has limited diagnostic value; serial (trending) measurements are far more informative.
• An elevated marker does not always indicate malignancy; a normal marker does not exclude it.
• "Tumour marker screens" or blanket "malignancy?" requests are actively discouraged - they are costly, cause patient anxiety, and have low yield without clinical context.
• High-dose hook effect: Extremely high concentrations of some markers can paradoxically give a falsely low result in immunoassays (important for hCG in choriocarcinoma).
• HAMA interference: Patients treated with mouse monoclonal antibodies may have human anti-mouse antibodies that cause false positives or negatives.
• Results should always be interpreted in the clinical context of the suspected/diagnosed malignancy and the treatment stage. - Tietz Textbook of Laboratory Medicine, 7th Ed.