Tumour Markers
Specificity and sensitivity
- The specificity of a test is a measure of the incidence of negative results in persons know to be free of the disease. It gives a ‘false positive’ result
- It is calculated as follows,
- Specificity = TN/ all without disease (FP + TN) x 100
- It is calculated as follows,
- The sensitivity of a test is a measure of the incidence of positive results in patients know to have the condition. It gives ‘false negative’ result
- It is calculated as follows,
- Sensitivity = TP/ all with disease (TP + FN) x 100
- It is calculated as follows,
- Factors that increase the specificity of a test tend to decrease its sensitivity and vice versa
- The ideal secreted tumour marker could be used for;
- Screening
- Diagnosis
- Prognosis
- Monitoring treatment
- Follow up to detect recurrence
- Screening
- Although some markers are reliable for some of these purposes only one CHORIONIC GONADONTROPHIN (a marker for choriocarcinoma) can be used for them all
α-Fetoprotein
- A glycoprotein that is synthesised by the yolk sac and fetal liver and gut
- In the fetus it is a major plasma protein, in the adult levels should be below 10μg/L
- Its levels increase during pregnancy and it is used in the diagnosis of neural tube defects
- It is also a marker for hepatocellular carcinomas and testicular teratomas
- Although HCC is rare in the general population, there are certain patients at high risk – those with cirrhosis, persistent Hep B and haemochromatosis – in whom screening may be helpful
- α-fetoprotein concentrations are raised in the majority of patients with cirrhosis and HCC, but only half of patients with HCC in the absence of cirrhosis
- A concentration >500μg/L is virtually diagnostic of HCC in a patient with cirrhosis
- A value of 50-500μg/L requires further investigation
- As a tumour marker it is not very specific as concentrations of up to 100μg/L can occur in cirrhosis in the absence of malignancy
- It is not of value prognostically but in confirmed cancer it is of use in monitoring response to treatment
- In testicular teratomas, measurements of α-fetoprotein are used for assessing prognosis, staging and monitoring therapy
- A very high concentration indicates a massive tumour load and a poor prognosis – mortality rate >40% if the concentration is >1.26mg/L
- A rapid fall to normal levels after orchidectomy implies the disease was limited to the testes
- Once a patient is in remission, repeated measurements are essential, a rise in concentration being due to recurrence of the tumour
- Teratomas comprise around 30% of all testicular tumours, the most common are seminomas (40%) but these rarely secreted either α-fetoprotein or β-hCG
Carcinoembryonic antigen (CEA)
- Present in the plasma of 60% of patients with colorectal cancer, more commonly so with advanced disease
- Elevated concentrations are also found in a variety of non-malignant conditions;
- Pancreatitis
- IBD
- Heavy smokers
- Pancreatitis
- CEA is neither sensitive or specific enough to be used for screening in colorectal cancer
- CEA concentrations correlate poorly with tumour bulk so is therefore not useful in measuring response to treatment
Paraproteins
- Detectable in the serum and urine of 98-99% of patients with myeloma
- Concentrations correlate well with tumour bulk and a reduction in the level of paraprotein is a good indicator of the efficacy of treatment
Human Chorionic Gonadotrophin
- hCG is produced by the normal placenta reaching a maximum concentration by the 8th week of pregnancy
- it is composed of an α and a β subunit, with the α subunit being identical to that of LH, FSH and TSH but the β subunit being specific to hCG
- The presence of hCG in the plasma at other times indicates the presence of abnormal trophoblastic tissue of a tumour secreting hormone ectopically
- It is an ideal tumour marker for choriocarcinoma, a malignant proliferation of chorionic villi which may arise from hydatiform mole, which occurs in 1 in 2000 pregnancies
- It can be used for diagnosis, response to treatment and for long term follow up
- hCG is secreted in around 50% of testicular teratomas
- Since LH concentrations rise after orchidectomy, it is important that an assay specific to the β-chain of hCG is used to avoid cross reaction
Prostatic Specific Antigen
Prostatic cancer is the second most common cancer in males
- PSA is a marker for this tumour
- PSA is a 33kDa serine protease, normally secreted into the prostatic duct system but small amount diffuse into the plasma and probably functions to help liquidise semen
- PSA concentrations tend to increase in prostatic cancer but the sensitivity and specificity of PSA as a marker are lmited by the fact that PSA;
- Is detectable in normal men
- Increases with age
- Increases with benign prostatic hypertrophy (BPH) and prostatis
- Is detectable in normal men
- Using a cut off of 4mg/L, specificity is 97% in men over the age of 40 and the sensitivity of stage I disease is 67%
- Approaches to improve the sensitivity and specificity of PSA measurements have included;
- Development of age related reference ranges
- Relating PSA levels to the prostatic volume as estimated by ultrasound
- Determining the rate of change over time
- Measuring free and bound PSA – while most PSA in the plasma of normal men is protein bound, the bound portion is higher in the presence of prostatic cancer whereas free PSA is higher in BPH
- Development of age related reference ranges
Carbohydrate antigen (CA) Markers
- Tumour marker which have been identified following attempts to develop monoclonal antibodies against tumour extracts of tumour cell lines
- They are high MW glycoproteins
- CA 125 is marker for ovarian cancer
- It can also be increased in non-malignant conditions e.g. endometriosis and ascites and other malignancies
- Its concentration at the time of diagnosis isn’t useful in prognosis but serial measurements are valuable in monitoring patients following surgery
- It can also be increased in non-malignant conditions e.g. endometriosis and ascites and other malignancies
- CA 199 is a marker of adenocarcinoma of the pancreas, colorectal and gastric tumours
- Levels are elevated in >80% of patients with carcinoma of the exocrine pancreas and only occasionally in benign disease
- Its potential value is limited however by the fact that pancreatic carcinoma tends to present late when no effect treatment is available
- CA 199 also increases in patients with primary sclerosing cholangitis and can be used to monitor disease activity
- Patients with this condition are at increased risk of developing cholangiocarcinoma and if this happens there is usually a rapid increase in CA 199 concentrations
- Measurement of CA 199 can be combined with that of CEA, which does not tend to be elevated in sclerosing cholangitis but does tend to rise in cholangiocarcinoma
- Levels are elevated in >80% of patients with carcinoma of the exocrine pancreas and only occasionally in benign disease
Hypercalcaemia of malignancy
- When bony metastases are present, dissolution of calcium from the bone by the metastases themselves may contribute to hypercalcaemia
- However hypercalcaemia can occur in the absence of metastatic disease
- True ectopic secretion of PTH is rare
- Parathyroid hormone-related peptide is the humoral factor most commonly involved. It has N-terminial amino acid sequence homology with PTH and binds to PTH receptors and has similar actions to PTH itself. It is most commonly produced by small cell carcinoma of the bronchus and renal adenocarcinomas
- Hypercalcaemia is also common in haematological malignancy particularly myeloma and is due to the release of osteoclast activating cytokines e.g. IL-1 and TNF-β by the tumours
- Osteoclasts may also be activated by prostaglandins produced by metastases in bone
Ectopic hormone syndromes
Ectopic ACTH syndrome
- May be produced by small cell carcinoma of the bronchus or carcinoid tumours
- The clinical presentation is often dominated by the metabolic sequelae of excessive cortisol secretion. This includes hyperkalaemia with alkalosis, myopathy, glucose intolerance, osteoporosis and hypertension
Ectopic ADH syndrome
- Most commonly seen with small cell carcinoma of the bronchus, carcinoid tumours and pancreatic adenocarcinomas
Causes water retention and dilutional hyponat