Tumour markers

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Tumour Markers

Definition

Tumour markers are substances - enzymes, hormones, proteins, oncofetal antigens, glycoproteins, or genetic material - that can be measured in blood, urine, or tissue and whose levels indicate the presence, activity, or behaviour of a neoplasm. They are surrogate indicators of cancer biology, useful when the tumour itself is not clinically detectable.

Robbins & Kumar Basic Pathology, p. 600
Sabiston Textbook of Surgery, p. 1221

The Ideal Tumour Marker

No currently known marker fulfills all three ideal criteria:

Expressed exclusively by the specific tumour
Specimen collection is easy (blood or urine)
Assay is reproducible, rapid, and inexpensive

In practice, most routinely used markers fall short on both sensitivity (they may be normal even in proven cancer) and specificity (they can be raised in benign conditions).

Sabiston Textbook of Surgery, p. 1220

Categories of Tumour Markers

Category	Examples
Whole cells	Circulating tumour cells (CTCs)
Proteins	PSA, CEA, AFP, CA-125, CA-19-9, CA-15-3, calcitonin, immunoglobulins
Hormones	hCG, calcitonin, catecholamines/metabolites, ectopic hormones
Oncofetal antigens	AFP, CEA
RNA-based	mRNA, miRNA, lncRNA (emerging, not yet FDA-approved for routine use)
DNA-based	ctDNA, EGFR/KRAS/TP53/APC mutants, gene fusions, epigenetic changes
Tissue markers	ER/PR, HER2, ALK, BRAF, KRAS (guide targeted therapy)

Sabiston Textbook of Surgery, p. 1221

Key Tumour Markers and Their Associated Tumours

Hormones

Marker	Associated Cancer
hCG (beta-hCG)	Trophoblastic tumours (choriocarcinoma), non-seminomatous testicular GCTs
Calcitonin	Medullary carcinoma of thyroid
Catecholamines/metabolites	Phaeochromocytoma and related tumours

Oncofetal Antigens

Marker	Associated Cancer	Notes
AFP (alpha-fetoprotein)	Hepatocellular carcinoma, yolk sac tumours, embryonal carcinoma	Also elevated in liver disease, pregnancy
CEA (carcinoembryonic antigen)	Colorectal, pancreatic, gastric, lung, breast carcinomas	Most useful single marker for adenocarcinomas

Glycoproteins / CA Antigens

Marker	Associated Cancer
CA-125	Ovarian cancer, fallopian tube cancer
CA-19-9	Pancreatic, colorectal, hepatobiliary, gastric cancers
CA-15-3	Breast cancer

Lineage-Specific Proteins

Marker	Associated Cancer
PSA	Prostate adenocarcinoma
Immunoglobulins (monoclonal)	Multiple myeloma and plasma cell tumours
LDH	Testicular GCTs (also non-specific - lymphoma, etc.)

Tissue/Molecular Markers (Theranostic)

Marker	Cancer	Utility
ER / PR	Breast cancer	Endocrine therapy selection
HER2	Breast, gastric cancer	Trastuzumab eligibility
KRAS / BRAF	Colorectal, melanoma, lung	Targeted therapy selection
ALK / EGFR	Non-small cell lung cancer	Targeted therapy
MYCN amplification	Neuroblastoma	Prognosis

Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 7.12
Tietz Textbook of Laboratory Medicine, p. 1055

Clinical Uses

Screening - Limited by low specificity; recommended only in high-risk populations (e.g. AFP for hepatocellular carcinoma, CA-125 for ovarian cancer in BRCA carriers)
Diagnosis - Rarely diagnostic alone; cannot replace biopsy
Staging / prognosis - e.g. LDH and hCG levels in testicular GCTs classify patients into IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic categories
Monitoring treatment response - Markers should fall with successful treatment; persistence indicates residual disease
Detecting recurrence - Reappearance after normalisation almost always signals tumour recurrence (classic example: rising CEA after colorectal resection)

Key Individual Markers in Detail

PSA (Prostate-Specific Antigen)

A glycoprotein produced by prostatic epithelial cells
Elevated in cancer, BPH, prostatitis, and after UTI
Artificially lowered up to 2-fold by 5-alpha-reductase inhibitors (finasteride, dutasteride)
Not significantly altered by DRE
After a UTI, takes 6 weeks to return to baseline
Primary value: monitoring recurrence after prostatectomy, not screening
Bailey and Love's Surgery, p. 1470

AFP (Alpha-Fetoprotein)

Normally produced by fetal yolk sac and liver; declines to near zero after birth
Elevated in: hepatocellular carcinoma, yolk sac tumours, some teratocarcinomas
Also raised in: hepatitis, cirrhosis, pregnancy, neural tube defects
Mandatory measurement in testicular GCT management

CEA (Carcinoembryonic Antigen)

Oncofetal protein produced by various carcinomas
Sensitivity ~50% for malignant effusions; specificity ~90% for leptomeningeal carcinoma metastasis
Most useful for post-operative monitoring of stages II and III colorectal cancer

hCG (Human Chorionic Gonadotropin)

Gold standard marker for trophoblastic disease and non-seminomatous GCTs
Together with AFP and LDH, used for IGCCCG staging of testicular cancer

CA-125

Raised in ovarian cancer but also endometriosis, PID, fibroids, and other benign conditions
Useful in monitoring, not screening

CA-19-9

Primarily pancreatic cancer marker; also colorectal and hepatobiliary
Not useful for general population screening due to low specificity

Limitations

A raised marker does not necessarily mean malignancy
A normal marker does not exclude malignancy (false negatives occur)
Elevated levels can occur in benign conditions (inflammation, organ disease, pregnancy)
Serial measurements are almost always more useful than a single result
Panels of markers improve sensitivity but at the cost of specificity
Opportunistic screening with marker panels in the general population is not helpful
Tietz Textbook of Laboratory Medicine, p. 1054

Emerging Markers (Liquid Biopsy)

The next frontier in tumour markers includes:

Circulating tumour DNA (ctDNA) - detects cancer-specific mutations in plasma
Circulating tumour cells (CTCs) - whole cell analysis
Methylation patterns - epigenetic markers
miRNA / lncRNA - RNA-based markers

These are not yet FDA-approved for routine clinical use, but data supporting their role as predictive and prognostic diagnostics is rapidly accumulating.

Sabiston Textbook of Surgery, p. 1221

Bottom line: Tumour markers are most valuable for monitoring disease response and detecting recurrence rather than primary diagnosis or general screening. Always interpret in clinical context, and confirm any decision-altering result on a repeat specimen.

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