PSA AND PROSTATE CANCER

PSA and prostate cancer
Until the development of commercial serum PSA assays in the late 1980s, the only serum marker for prostate cancer was acid phosphatase. This was highly specific for prostate cancer metastatic to bone, but lacked sensitivity in detecting less advanced disease and was even normal in >20% patients with bone metastases.

Prior to the PSA era, most men with newly diagnosed prostate cancer had advanced incurable disease. PSA has revolutionized the diagnosis and management of prostate cancer, although its use in screening and early detection remains controversial. In addition to its use as a serum marker for the diagnosis of prostate cancer, PSA elevations may help in staging, counselling, and monitoring prostate cancer patients. Here are some examples:
- PSA generally increases with advancing stage and tumour volume, although a small proportion of poorly differentiated tumours fail to express PSA.
- PSA is used, along with clinical (DRE) T stage and Gleason score, to predict pathological tumour staging and outcome after radical treatments using statistically derived nomograms and artificial neural networks.
- >50% of patients have extra-prostatic disease if PSA >10ng/ml.
- <5% of patients have lymph node metastases and only 1% have bone metastases if PSA <20ng/ml.
- 66% of patients have lymphatic involvement and 90% have seminal vesicle involvement if PSA >50ng/ml.
- PSA should be virtually undetectable following radical prostatectomy for gland-confined disease.
- PSA rise after radical prostatectomy precedes the development of clinical metastatic disease by a mean time of 8 years.
- PSA falls to within the normal range in 80% of patients with metastatic disease on hormone therapy within 4 months; the PSA rises in a mean time of 18 months after starting hormone therapy, signalling progressing disease.

PSA is prostate-specific, but sadly not prostate cancer-specific. In the presence of infection or instrumentation, PSA should not be requested until at least 28 days after the event, to avoid a false +ve result causing unnecessary concern to doctor and patient. Ideally, PSA should not be requested within 2 days of ejaculation or DRE, but in practice it makes negligible difference to the result.

PSA derivatives: free-to-total ratio, density, and velocity
Measurement of the free-to-total (F:T) PSA ratio increases the specificity of total PSA because the ratio is lower in men with prostate cancer than in men with benign hyperplasia. This may be helpful in deciding whether to re-biopsy a patient with previous benign biopsies. While, overall, a man with a normal DRE and a PSA of 4 - 10ng/ml has a 27% risk of prostate cancer, this risk rises to 60% if the F:T ratio is 10% and falls to 10% if his ratio is >25%. The F:T ratio may also be useful in the total PSA range 2.5 - 4ng/ml. Chronic prostatitis may also cause a reduced F:T ratio.

An important limitation of this investigation is the instability of free PSA. The serum must be assayed within 3h or frozen at -20°C, otherwise the free component reduces and a low ratio will be reported. There is considerable interest in the more stable complexed PSA concentration, although it cannot yet be used alone.

Consideration may be given to the prostate volume, since large benign prostates are the most common cause of mildly elevated PSA. Serum PSA/prostate volume = PSA density, and serum PSA/prostate transition-zone volume = PSA-TZ density. Various cut-off densities have been proposed to raise the specificity of total PSA, possibly to reduce the need for prostatic biopsy, but the issue remains controversial.

Short-term variations in serum PSA occur in the presence or absence of cancer, the cause of which may be technical or physiological. Longer term, the PSA tends to rise slowly due to BPH and faster due to prostate cancer PSA velocity. A PSA velocity >0.75ng/ml per year over at least 18 months in total PSA range 4 - 10ng/ml is suggestive of the presence of PC, given that only 5% of men without cancer exhibit such a velocity. A PSA velocity >20% per year should also prompt the recommendation of a biopsy, although a slower velocity does not exclude the presence of cancer. The use of PSA velocity is an option for the patient who wishes to avoid an initial or repeat prostatic biopsy.