Tumour Markers Flashcards
Definition of Tumour Marker
substances produced by tumour cells or by the host in response to a tumour
used to detect presence of tumour
can be found in cells, tissue or body fluids
measurable qualitatively or quantitatively
Sensitivity and Specificity
tests that are closer to the genetic basis of cancer are more sensitive and specific
DNA (BCR-ABL, HER2, EBV DNA) – Strange proteins (AFP, CEA, CA125, CA19-9) – Hormones (ADH, PTHrP, ACTH, hCG) – Tissue markers (PSA, Thyroglobulin) – General biochemical changes (LRFT, electrolytes, urate, LDH, ferritin etc)
Tumour specific = specific for single individual tumour
Tumour associated = found in different tumours of the same tissue type
Characteristics of an Ideal Tumour Marker
High sensitivity and specificity (organ specific)
Levels correlate with mass, severity, prognosis
Short half-life for rapid monitoring
Discriminatory to identify tumour from benign to healthy states
Adequate lead time for early diagnosis and Tx
==> screening, diagnosis, prognosis, monitoring, prediction of treatment response, detection of recurrence or relapse
Principles of screening and benefits/ risks
Principles:
- important health problem with accepted treatment, available facilities for Dx and Tx, recognisable latent or early symptomatic stage, suitable test that is acceptable to population, natural history of the condition is well known, established policy on who to treat, balance with costs
Benefits:
- improved prognosis
- less radical treatment needed for early disease
- reassurance if -ve
Risks
- longer morbidity
- over-treatment
- false reassurance if false negative
- anxiety and morbidity if false positive
Alpha-Fetoprotein (AFP)
Glycoprotein (heterogenous with varying degrees of glycosylation)
- one of the major proteins in foetal circulation
- synthesised by foetal liver and yolk sac
Produced by:
- HCC (esp AFP-L3 type)
- NSGCT (non-seminomatous germ cell tumours)
- Hepatoblastoma (in children)
- other types of advanced ADC
Uses:
- NSGCT - diagnosis, staging and monitoring (along with hCG and LDH); NOT FOR SCREENING
- HCC and Hepatoblastoma - aid Dx, monitoring and prognosis; SCREENING FOR HCC IN HIGH RISK, not in general population; NOT FOR METASTASIS
Interpretation of AFP
t1/2 = 5 days
Ref value: <10 microgram/L in healthy and non-pregnant
Screening in high risk for HCC
- surveillance with 6 monthly AFP and USG
- > 20 with rising trend = further Ix needed
- > 200 suggestive of HCC (virtually diagnostic if USG lesion >2cm present)
- > 400 = HCC if with any suspicious lesion
- > 1000 = symptomatic HCC patients
(most benign liver diseases <200)
Pregnancy
- maternal AFP increase from 12 wks, peak at 500 in 3rd trimester
- fetal AFP peak at 2 million at 14 wks and declines to 70000 at term
Infants
- extremely high (>10000)
- fall to adults levels between 6 mths and 1 yr – static levels may suggest underlying pathology
DDx of elevated AFP
Physiological
- infants
- pregnancy
Benign
- congenital disorders e.g. down’s
- childhood (citrin deficiency)
- liver cirrhosis, hepatitis, biliary tract obstruction, alcoholic liver disease, DILI
Malignant
- hepatoblastoma (children)
- NSGCT
- HCC
- other advanced ADC
Carcinoembryonic Antigen (CEA)
Cell-surface glycoprotein (also heterogenous in size)
- found in variety of normal and malignant epithelial tissues in GI, H&N, Lung and Breast
- also in foetal intestine, liver and pancreas
- may potentiate invasion and metastasis
Uses:
- post-treatment SURVEILLANCE of CRC –> serum CEA levels correlate with disease burden and is prognostic; NOT FOR SCREENING
- monitoring of other cancers as a tumour associated marker (metastatic cancers)
Interpretation of CEA
t1/2 = 3 days
Ref values: <3 mcg/L in non-smokers; <5 mcg/L in smokers
- non specific; benign conditions rarely cause CEA >10
- post-operative CEA elevation indicates recurrence with high probability
DDx of elevated CEA
Benign
- colon: IBD, polyps
- others: hepatitis, cirrhosis, alcoholic liver disease, obstructive jaundice, peptic ulcers, pancreatitis, bronchitis, renal, benign breast disease
Malignant
- colon: CRC
- others: CA lung, breast, stomach, pancreas, H&N
Human Chorionic Gonadotrophin (serum hCG)
Glycoprotein hormone (heterodimer with alpha and beta subunit – alpha similar to LH, FSH and TSH; beta unique)
Synthesised by syncytiotrophoblasts of placenta during pregnancy (maintain progesterone production of corpus luteum)
Produced by:
- germ cell tumours (e.g. testicular cancer) and trophoblastic diseases (hydatidiform mole, choriocarcinoma)
hCG secreted by tumours may be heavily glycosylated
Uses:
- diagnosis, follow up and prognosis in cancers
(also prenatal testing)
Interpretation of serum hCG
t1/2 = 36-48 hrs
Ref values: premenopausal, non-pregnant <1 IU/L; post-menopausal women <7; men <2
- serum hCG can be up to 25 in menopause
DDx of elevated hCG
Benign
- pregnancy
- pituitary hCG
- injection of hCG
- assay interferences
Malignant
- germ cell tumour (gonadal and extra-gonadal)
- gestational trophoblastic diseases (choriocarcinoma, hydatidifom mole)
- non-trophoblastic cancer (gyn, breast, GI, lung, GU, haematopoietic)
Prostate Specific Antigen (PSA)
Glycoprotein (serine protease)
- various molecular forms due to complex formation with protease inhibitors
- most PSA exists as COMPLEXED form; 10-30% free PSA
Produced EXCLUSIVELY by epithelial cells of acini and ducts of prostate gland
Uses:
- CA prostate – aid diagnosis, prognosis, surveillance, monitoring; SCREENING in men >50 yrs (value used is controversial)
Interpretation of PSA
t1/2 = 2.5 days after radical prostatectomyy
Ref values: total PSA <4 mcg/L; age specific values may give higher clinical sensitivity
<2.5 in 40-49
<3.5 in 50-59
<4.5 in 60-69
<6.5 in 70-79
Transient elevation in urological manipulation e.g. TURP, needle biopsy
– wait at least 6 weeks before testing!
PSA assays
measure free and complexed PSA (i..e total PSA)
traditional cutoff of 4 mcg/L has 30% PPV (many patients with +ve test won’t have CA on biopsy)
Most CA detected within “gray zone” 4-10 mcg/L are organ confined and potentially curable
Additional measurements to improve diagnostic performance
- PSA velocity (high = higher risk)
- PSA density (high)
- % free PSA (low)
- p2PSA (high)
- **Prostate Health Index (PHI) - using p2PSA, fPSA and total PSA
PHI as a rule out test to avoid unnecessary biopsies in patients with PSA 4-10 and normal DRE
DDx of elevated PSA
Benign
- prostate: BPH, prostatitis, UTI, urinary obstruction
- pre-analytical factors: DRE, ejaculation, invasive procedures, prostate massage
Malignant
- CA prostate
Cancer Antigen 125 (CA 125)
3 categories of ovarian tumours: epithelial cell, sex-cord, germ cell
- serous type of epithelial tumours are majority of primary ovarian cancers
Large transmembrane glycoprotein contributing to physical barrier of cell and transmission of signals
MUC16 gene coding for protein mucin 16
- expressed by mullerian epithelia (Fallopian tube, tubal, endometrial, endocervial) and coelomic epithelia (pericardium, pleura, peritoneum)
Uses:
- ddx of pelvic masses
- monitoring, detection of recurrence and prognostic indicator in known cancer
- SCREENING in patients at risk of hereditary syndromes, with transvaginal USG
- NOT FOR ASYMPTOMATIC
Interpretation of CA 125
t1/2 = 5-7 days
Ref values: <35 kU/L
CA 125 may increase during menses
Diagnostic performance:
- menopausal status: mainly useful in postmenopausal women
- type of cancer: 80% epithelial ovarian cancer have CA 125 >35
- stage of cancer: elevation of 50% in stage I disease; 90% in stage II, >90% stage III and IV
DDx of elevated CA 125
Benign - benign ovarian neoplasms - endometriosis - PID - pregnancy - menstruation (and many other benign gyn conditions)
Malignant
- epithelial ovarian cancer
- Fallopian tube cancer
- primary peritoneal cancer
(and LOTS of other benign and malignant non-gyn diseases of liver, colon, lung etc.)
Assessment of Adnexal Mass
(growth in or near uterus/ ovaries/ Fallopian tubes and connecting tissues)
CA125, Human epididymis protein (HE4), Menopausal status (M), USG findings (U)
Risk of malignancy algorithm: CA125, HE4, M
Risk of malignancy index: U, M, CA125
Cancer Antigen 15-3 (CA 15-3)
Large transmembrane glycoprotein encoded by MUC1 gene
Uses:
- CA breast: management, detect recurrence, monitoring treatment response in metastatic disease
- NOT FOR SCREENING
Interpretation of CA 15-3
Ref value: <30 kU/L; >5x cut-off value suggests metastatic disease
DDx of elevated CA 15-3
Benign
- breast: benign breast disease
- others: benign liver disease
Malignant
- breast: CA
- others: lung, colon, liver, pancreas, ovary
Thyroglobulin
Glycoprotein stored in follicular colloid
EXCLUSIVELY produced by thyroid cells
Uses:
- CA thyroid RECURRENCE after total thyroidectomy and RT ablation (detectable or increase from stable levels = further Ix needed); NOT FOR DIAGNOSIS
- detect factitious thyrotoxicosis in thyrotoxic patients
Interpretation of Thyroglobulin
TSH and Anti-thyroglobulin Ab required for interpretation (may interfere with assays - false negatives)
- TSH >30 mIU/L = stimulated thyroglobulin (more sensitive) –> thyroglobulin >2 mcg/L needs prompt Ix and Mx (recurrence or persistence of remnant normal thyroid tissue)
- TSH <0.1 mIU/L = unstimulated –> high sensitivity thyroglobulin assay required
Markers of endocrine tumours
Phaeochromocytoma - urine metanephrines, catecholamines
Neuroblastoma - VMA
Carcinoid - urine 5-HIAA
SCLC - ectopic ACTH, SIADH
Pituitary adenoma - prolactin, GH
Medullary thyroid CA - calcitonin
Neuroendocrine - insulin/ VIP/ gastrin etc.
Paraproteins
Monoclonal Ig
Bence Jones Proteins
Molecular markers
Breast and ovary CA
- BRCA-1, erbB-, p53
CML and AML
- ABL
Burkitt
- MYC
Medullary thyroid CA (MEN2)
- RET
NPC
- plasma EBV DNA
Clinical Applications
Screening
- population-based: FOBT for CRC in all >50 yrs; PSA for all men >50 yrs
- high risk grp (+ve FHx): FOBT, PSA in men >40 yrs, CA 125, Calcitonin, AFP if chronic Hepatitis B
Diagnosis
- aid in high risk grps e.g. AFP for HCC
- differentiate benign and malignant adnexal mass using CA 125 to calculate risk of malignancy index
Prognosis
- AFP, hCG, LDH for metastatic NSGCT
Prediction of Tx response
- invasive CA breast: ER, HER2
Monitoring Tx response
- CA 125 decrease by 50% in ovarian CA treatment
- CEA in patients receiving chemo for CRC with liver metastasis
Detection of recurrence
- CEA after non-metastatic CRC curative surgery
