Tumour markers

What tumour markers can and cannot do

Tumour-associated, not tumour-specific - almost every marker is raised by benign disease
*Their value is in monitoring a known cancer, not in finding one*
The exceptions that genuinely aid diagnosis: AFP/beta-hCG in germ cell tumours, AFP in HCC surveillance, calcitonin in medullary thyroid carcinoma, EBV DNA in nasopharyngeal carcinoma

No tumour marker is used for population screening in Australia
PSA is offered with shared decision-making, not as a program
CA-125 screening in average-risk women does not reduce ovarian cancer mortality (UKCTOCS)

Most are oncofetal antigens (CEA, AFP), mucins (CA-125, CA19-9, CA15-3), hormones (beta-hCG, calcitonin) or enzymes (PSA, LDH, ALP)
Raised by production and by impaired clearance
- CA19-9 is cleared in bile - obstructive jaundice alone raises it dramatically
- CEA raised by smoking, cirrhosis, IBD, pancreatitis
CA19-9 requires the Lewis antigen: 5-10% of people are Lewis-negative and never express it - a false negative by genotype

Marker	Cancer	Also raised in
CEA	Colorectal (also lung, breast, pancreas)	Smoking, cirrhosis, IBD, pancreatitis, PUD
CA19-9	Pancreas, biliary, gastric	Obstructive jaundice, cholangitis, pancreatitis. Absent in Lewis-negative
CA-125	Ovarian	Any peritoneal irritation - endometriosis, fibroids, PID, menstruation, pregnancy, cirrhosis, heart failure, TB
CA15-3 / CA27.29	Breast - monitoring response and recurrence	Benign breast disease, liver disease
PSA	Prostate	BPH, prostatitis, instrumentation, ejaculation, cycling
AFP	HCC; NSGCT (yolk sac, embryonal)	Cirrhosis, hepatitis, pregnancy. *Never raised by pure seminoma*
beta-hCG	Germ cell tumour, gestational trophoblastic neoplasia	Pregnancy; may be raised in seminoma AND non-seminoma
LDH	Cell turnover - melanoma, germ cell, lymphoma	Haemolysis, infarction, hepatitis, muscle injury
ALP	Bone metastases, cholestasis	Paget's, growth, pregnancy (placental)
Chromogranin A	Neuroendocrine tumours	*PPIs* (a very common false positive), renal failure, atrophic gastritis
Calcitonin	Medullary thyroid carcinoma	Renal failure, PPIs
Thyroglobulin	Differentiated thyroid Ca (post-thyroidectomy)	Anti-Tg antibodies invalidate it
CA72-4	Gastric	-
Beta-2 microglobulin	Myeloma (prognostic, in ISS)	Renal impairment

AFP + beta-hCG + LDH together give stage, IGCCCG risk group, and response
AFP raised = a non-seminomatous component is present, whatever the histology says - treat as NSGCT
Post-orchidectomy half-lives: beta-hCG 1-3 days, AFP 5-7 days
- Failure to fall as predicted = residual disease

A. Monitoring treatment response - the commonest valid use
B. Surveillance for recurrence - CEA after colorectal resection; thyroglobulin after thyroidectomy; EBV DNA after nasopharyngeal carcinoma
C. Prognostication/staging - LDH in melanoma and lymphoma; beta-2 microglobulin in myeloma; AFP/hCG/LDH in germ cell tumours
D. Diagnosis (rarely) - germ cell tumours, HCC with a classic lesion, medullary thyroid carcinoma

*Do not order a tumour marker unless you know what you will do with either result*
Baseline before treatment - a marker that was never raised cannot be used for monitoring
Interpret trends, not single values; use the same assay and laboratory
Do not act on an isolated rise - repeat in 4-6 weeks and correlate with imaging
Do not use tumour markers to work up an unknown primary in place of histology
Rising CA-125 alone in ovarian cancer should NOT trigger earlier chemotherapy - MRC OV05 showed no survival benefit and worse quality of life
Never diagnose cancer on a marker alone - tissue is the diagnosis

Obstructive jaundice -> CA19-9
Cirrhosis and chronic hepatitis -> AFP
Endometriosis, fibroids, ascites, heart failure, cirrhosis -> CA-125
Smoking -> CEA
PPIs -> chromogranin A and calcitonin (stop for 2 weeks before testing)
Renal impairment -> beta-2 microglobulin, calcitonin, chromogranin A
Pregnancy -> AFP, beta-hCG, placental ALP
Heterophile antibodies -> false positive beta-hCG ("phantom hCG" - check urine hCG, which will be negative)
Anti-thyroglobulin antibodies -> falsely low thyroglobulin

Marker doubling time correlates with tumour growth rate (PSA doubling time is the strongest prognostic tool in biochemical recurrence of prostate cancer)
Marker flare: transient rise in the first weeks of effective therapy from cell lysis - do not misinterpret as progression
Markers may become uninformative if the tumour dedifferentiates and stops secreting (neuroendocrine transformation of prostate cancer - PSA falls while disease progresses)
False reassurance from a normal marker is the commonest clinical harm; false alarm from a benign rise is the second

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