History
A male aged 68 years presented to his GP with dysuria. On direct questioning, he admitted to nocturia twice nightly and some urgency of micturition. On rectal examina-tion, the prostate was enlarged and the patient complained of discomfort during this examination. The GP arranged for a midstream specimen of urine (MSU) and blood tests, including prostate-specific antigen (PSA) which were taken the following morning.
Investigations
Investigation revealed:
Midstream specimen of urine, no growth
Full blood count (FBC), slight increase in neutrophils.
Initial findings 6-week follow-up findings
Reference range
Sodium 142 mmol/L 138 mmol/L 135–146 mmol/L
Potassium 4.2 mmol/L 3.9 mmol/L 3.2–5.1 mmol/L
Creatinine 112 μmol/L 95 μmol/L 62–106 μmol/L
Urea 9.2 mmol/L 8.5 mmol/L 1.7–8.3 mmol/L
Estimated glomerular
Free PSA 15% 18% <15%
C-reactive protein (CRP) 22 mg/L <5 mg/L
The following week he was admitted via A&E with fever and rectal pain. Blood cultures were positive and a diagnosis of prostatitis was made. Intravenous antibiotics were infused over a 2-week period followed by oral therapy.
He was discharged from hospital and 6 weeks after admission his blood tests were repeated as above.
QUESTIONS
1. What is the half-life of circulating PSA?
2. Was the first PSA a true reflection of his cancer risk? Explain your reasoning.
3. Was his second PSA a true reflection of his cancer risk? Explain your reasoning.
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4. Which circumstances may cause the serum PSA to be elevated?
5. What percentage of free PSA indicates a high probability of malignancy?
6. What is the reason for the age-related reference range for PSA?
7. What are the potential clinical uses of tumour markers?
8. What are the limitations to the use of tumour markers?
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88 Section 1: Clinical Chemistry
ANSwERS
1. The circulating half-life of PSA is 2.2–3.2 days, although the half-life of free PSA is much shorter – possibly less than 0.5 days. Following radical prostatectomy, serum PSA values should become undetectable by 3 weeks post-surgery.
2. The blood sample for PSA was taken the day after rectal examination. Although normal rectal examination is usually not associated with any significant increase in PSA levels, it is good practice to take a blood sample for PSA before undertaking a rectal examination of the prostate or waiting for a week after examination. In this patient, it seems likely that he had prostatitis at the time of examination and for this reason the PSA cannot be taken as a reliable indicator of malignancy.
3. This is more problematic. Because of the half-life of PSA, a serum level cannot guarantee to be unaffected by any manipulation or infection of the prostate for 2–3 weeks after the event. The unresolved question is how long following prostatitis do prostatic cells stop being damaged and tissue repair processes completed. The per-sistence of an elevated CRP value indicates an on-going inflammatory process. If the results were normal (both total and percentage free PSA) at 6 weeks then cancer can be excluded.
4. Prostatitis, sexual intercourse, digital rectal examination, riding a bicycle and urinary retention may all cause elevated serum PSA concentrations. The duration of increase following digital rectal examination, ejaculation and riding a bicycle is short term.
5. The percentage of free PSA (fPSA) indicates a high probability of malignancy when it is less than 15 per cent. Free PSA as a percentage of total PSA is a better marker of malignancy than total PSA. Although prostate cancer tissue has a PSA level about ten times greater than that of either normal or hyperplasic tissue, the clini-cal specificity and sensitivity of serum PSA as a test for the presence of cancer is poor. The majority of serum PSA is bound to either alpha-2-macroglobulin or alpha-1-antichymotrypsin. The ratio of free PSA to total PSA is inversely related to the likelihood of prostate cancer. Depending on age, digital rectal examination and total PSA, a patient with a free:total PSA ratio of less than 0.15 (free PSA <15 per cent of total) should generally be referred for further investigation. The higher the ratio the more likely it is to be due to benign prostatic hypertrophy, however there is considerable overlap and clinical considerations should take precedence over fPSA when making a diagnosis. The percentage free PSA in patients with slightly elevated total serum PSA has a higher sensitivity and specificity than total PSA.
6. The volume of the prostate increases with age and therefore the amount of PSA it produces. Hence, the reference range for PSA increases with age.
7. Caution is indicated in considering the value of measuring tumour markers, although there are many potential uses including:
a. Assistance in diagnosis: There needs to be a significant pre-test probability of a given malignancy for the use of tumour markers in the diagnosis of malignancy.
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A strong family history, as well as individual clinical presentations and findings will provide a probability.
b. Staging: The level of elevation may assist in determining spread of malignancy.
c. Determining prognosis: Markers may be an indication of tumour aggressiveness.
d. Guidance for intervention/predicting response to treatment: HER-2-positive breast cancer is more likely to respond to herceptin.
e. Monitoring response to therapy: When tumour markers are elevated before initiating treatment, then a reduction in concentration following surgery, radiotherapy or chemotherapy indicates a reduction in tumour mass.
f. Determining recurrence after treatment: When a tumour marker has fallen after treatment, but then rises again, this is an indication of local or more widespread recurrence.
8. Indiscriminate use of tumour markers indicates that the limitations of these assays have not been considered. They include:
a. Lack of specificity for malignancy: No tumour marker is 100 per cent diagnostic for malignancy. Many other disorders and even physiological variations (e.g. serum CA 125 increases with benign ovarian cysts and with menstruation) are associated with elevated serum concentrations.
b. Lack of organ specificity: With the possible exception of PSA, tumour markers are not organ specific.
c. Serum markers are not efficient at detecting early disease: In general, tumour markers are more likely to be elevated with disseminated malignancy. The posi-tive predicposi-tive value of serum carcinoembryonic antigen (CEA) in colon cancer is greater in Duke C and D than in stages A and B.
d. Lack of sensitivity: With the possible exception of hCG (human choronic gonadotrophin) in choriocarcinoma, no tumour marker is positive in all cases diagnosed.
e. Determining cause of malignancy: Blanket use of tumour markers when attempting to ascertain the source of malignancy is not an effective use of resources.
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