Prostate Specific Antigen: Discuss its use in prediction, detection and monitoring in prostate cancer.
The widespread using of prostate specific antigen (PSA) as a screening marker has generated a huge impact on the diagnosis and management of prostate cancer. Although the PSA testing coupled with digital rectal examination (DRE) had allowed the physicians to detect the presence of prostate tumours, however, there is no specific cutoff values of the amount of PSA levels to determine prostate cancer that had generated a controversy on the physicians are treating insignificant cancers.
It is a member of the human kallikrein gene family, PSA is a 33-kilodalton serine protease secreted by the prostatic epithelium and the epithelial lining of the periurethral glands. Its role is significant in the liquefaction of the seminal coagulum to allow the release of spermatozoa (1).
The prostatic lumen contains the highest concentration of PSA in the body and significant barriers, including the prostatic basement membrane, the intervening stroma, the capillary basement membrane and endothelial cell are introduced between the prostatic lumen and the capillary blood which prevent the leakage of PSA into the blood. As the disease progresses, these protective layers are compromised, allowing the escape of PSA and as a result, prostate cancer, prostatitis and prostatic intraepithelial neoplasia may be discovered from the patient. (10-12)
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According to the American Cancer Society, the estimated deaths from prostate cancer are 10% out of 294,120 men. Overall, cancer incidence rates are higher in men than women. Among the men, African Americans have the highest incidence of cancer followed by white men, Hispanic, Asian America. The American Cancer Society recommends that the PSA screening test should be offered annually accompanied by digital rectal examination at the age of 50, to have a life expectancy of 10 years and African American men who had a family history of prostate cancer should begin screening early at the age of 45years.
According to the Cancer Research UK, it states that prostate cancer is the most common cancer in men and it accounts for nearly a quarter (24%) of new male case diagnosis. There is a huge surge in the number of incidence cases due to the accidental discovery of prostate cancer through the method of transurethral resection of prostate (TURP) and also the use of prostate specific antigen (PSA). There are risk factors that will increase the men’s chances of having prostate cancer. The risk factor at the top of the list will be age, with low risk in men with age below 50, with highest risk at an increasing age. The older the man, the higher the risk with 80% of men by age 80 were shown to have prostate cancer cells (28).
The next strongest risk factor will be family history. It has been estimated that 5-10% of the prostate cancer cases and 3-40% of early-onset cases where men are diagnosed younger than 55years of age are caused by inherited susceptibility genes (29, 30).
Other risk factors include diet, such as foods that contain lycopenes and selenium and foods that contain high amount of calcium may increase risk and lifestyle habits, e.g. alcohol and smoking though may not posed a big effect on the incidence of prostate cancer but probably play a small part.
According to the Singapore Cancer Registry, and the article obtained from the Straits Times, Singapore, published on 1 March 2008, the incidence of prostate cancer has risen from a previously 5th commonest cancer among men in Singapore to the 3rd commonest cancer. In Asia, the incidence of the prostate cancer is much lower and therefore, there are not much large studies being done. With reference to the Clinical Practice Guidelines published by the Ministry of Health (MOH) in 2003 (31), recommendations to offer screening to men age above 50years and also to accompany the PSA testing with a digital rectal examination (DRE).
Prostate Specific Antigen (PSA) and its use in screening
The widespread use of PSA in clinical settings did not begin until the mid – 1980s, and before the introduction of PSA, prostatic acid phosphatase (PAP) were used as tumour marker for prostate cancer. Although PAP was useful in monitoring patients with advanced stage of the disease, however the low sensitivity in localized disease decreased its use as a screening marker for prostate cancer. (2) The initial usage of PSA as a screening marker came about due to its improved sensitivity over PAP. (3, 4)
Always on Time
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It has been known that increased PSA levels detected could meant that there could be an increased chance of the patient having prostate cancer, and it would prompt a recommendation that the patient undergo prostate biopsy with PSA of 4ng/mL as the traditional threshold level. The threshold level of 4ng/mL has often been criticized for being too relax and too strict on some occasions. It had been reported in numerous studies that prostate cancer is not uncommon in men with PSA values of <4ng/mL. An example taken from the Prostate Cancer Prevention Trial (PCPT), in an analysis of 2950 PCPT participants randomized to the study’s placebo group and who had a PSA level <4ng/mL or a normal digital rectal examination (DRE), it had been found that PSA levels of 0-4.0ng/mL were associated with a positive predictive value of between 6.6-26.9%. Overall, 14.9% of men with prostate carcinoma were found to have high grade disease, with a rate reaching up to 25% among men with a PSA level of 3.1-4.0ng/mL.
PSA and its use in prediction
The ability of making use of a screening marker to be able to predict the chances of having a cancer in the future is important and can certainly improve many lives and of course, providing treatment before the thingy and also reducing the mortality. Prostate specific antigen is one of the many markers that had been looked and researched into not being as a detection marker for prostate cancer but also as a marker for prediction and also the monitoring marker after treatment for prostate cancer.
PSA which is specific to the prostate but not only to prostate cancer, and in many cases, men with benign prostate hypertrophy (BPH) can cause a significant increase in the level of serum PSA and most men with increased PSA do not progressed to prostate cancer. Therefore, by being dependent only on PSA to predict the future of having prostate cancer is not feasible, digital rectal examination, PSA velocity and PSA density had been suggested to be conducted hand in hand to either predict or screen for prostate cancer.
Currently, there has been no definite level of PSA values that will determine if a man are at a higher risk of prostate cancer or already had signs of having prostate cancer. However, there is a level of 4.0ng/mL that had been used by the physicians as a threshold level, but this threshold level had been criticized as being both too lax and too strict.
On the other hand, there had been studies shown that if the man had previously shown modest but high levels of PSA, he is definite at a higher chance of having prostate carcinoma. In men who progress from a benign stage to advanced prostate cancer, there is always an inevitable an increased in the PSA level, and at most of the times, this elevation of PSA levels exceeds the generally slow increase of PSA levels observed in healthy men over a period of time. (32)
Researchers at the Johns Hopkins University had observed that if a man’s PSA rose at a rate greater than 0.75ng/mL per year, he was at an increased risk of being diagnosed with prostate cancer and in this study, it was noted that PSA determinations were separated by a minimum of 7 years. (33)
PSA density is another effort that may help to enhance the PSA specificity by adjusting for that component of the serum PSA that may arise from benign conditions. PSA density is a derivative measure that includes the division of serum PSA level by the volume of the prostate. The largest determinant of prostate size is the transition zone, with expansion resulting from the development of benign prostatic hypertrophy. (5) However, there is a discrepancy by using PSA density as a predictor of prostate cancer. A diagram may illustrates that although with a same amount of serum PSA in both men, but having a gland half as large as the other gland, it would be easier to assume that the carcinoma is more prevalent in the man with a small prostate, with an equal number of prostate biopsies obtained from both glands. It is more likely to miss the carcinoma in the larger gland due to sampling constraints while identifying the carcinoma in the smaller gland. (34)
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PSA have often been used as a single cutoff level for all ages which may seem to be inappropriate in many cases. As men progresses into older age, there is a tendency of having BPH (benign prostatic hyperplasia) where the prostate enlarges, and there is an increase of PSA present in the blood stream, even though there is no prostate abnormality.
Therefore by making use of a single cutoff value to determine if the man had prostate cancer would be deemed as inaccurate, thus resulting in unnecessary worries to the patients.
Some researchers have suggested having different PSA values for different age groups so as to be fair, however, this area still needs more study and research to prove the usefulness of age specific ranges.
A study had been done on a number of Jordanian men with different age groups for PSA testing.
Researchers such as Osterling and associates and Dalkin et al proposed a range of cutoff values of PSA for different age groups. Therefore, by making use of different ranges of PSA values, some men will be spared from unnecessary biopsies.
PSA performance varies among the different ethnicities. Most of the researchers had found that the PSA value is found higher in African-American men as compared to the White Americans (6-8), although there were some studies that had found none of the increased of PSA value (9) therefore, by decreasing the cutoff PSA value in testing the African-American men, sensitivity to the PSA test would be increased.
These studies done in the Western countries may not be applied to the Asian countries due to the lifestyle of the people and the body architecture between the Asians and Caucasians. With these considerations, a study was carried within a span of 4 years to find out the optimal PSA values detection in Chinese men without prostate cancer. Through the data collected and also comparing with data from other studies done on other Asians, it had been clear that from the age of 40 onwards, the PSA values increases steadily and the PSA values do not differ much from the Koreans and Japanese except for the age group of 70 and above, where the PSA values differ by more than 1.0ng/mL. However, if the values from the Japanese were to compare with the Asian Americans, then it is clear that the Asian Americans had a high value of PSA from age 50 onwards, since both groups are Asians, but yet the values differ from each other by more than 1.0ng/mL, then the factors affecting the increase in PSA values could be due to the diet, environment or some other unknown factors. Therefore, from Oesterling et al, the suggested range of age specific values for detection of prostate cancer could be only be applied to between ages of 40 and 69 years as their upper limits are quite close to one another, but for the age group of 70-79, the limits of the PSA values were much lower in the Chinese study (5.7ng/mL), so the Chinese patients with a PSA value of 5.37 to 6.5ng/mL would be missed if the criteria to be used for a prostate biopsy is at 6.5ng/mL according to the Oesterling et al. (10-14)
Table 1: A comparison of PSA values between men from different countries
Oesterling et al15
Table 2: Comparison of PSA values
Serum PSA has become the most useful and important marker in detecting prostate cancer, however, the low specificity limits it usefulness. Other conditions, like benign prostatic hyperplasia, may also cause an increase in PSA values which may result in unnecessary biopsies being carried out in men with a PSA value more than 4.0ng/mL where they may not have prostate cancer.
Therefore, with the rate of change in PSA levels over a period of time, or also known as PSA velocity (PSAV) has become a method to be investigated in order to improve the specificity of the PSA assay. In a study of PSA velocity from the Baltimore Longitudinal Aging Database, Carter et al mentioned that in 72% of the men with prostate cancer, they had a PSA velocity of more than 0.75ng/mL, whereas the PSA velocity of more than 0.75ng/mL is only seen in 5% of the men without prostate cancer. It was also reported that the obvious differences of PSA velocity in men with and without prostate cancer could be only detected up to 5 years before prostate cancer diagnosis.
Free and Complexed PSA
As mentioned before, PSA is a serine protease and a member of the human kallikrein family. It is now widely used as a tumour marker for prostate cancer. Although PSA is widely used and probably the most reliable marker, there is a need to search for markers that could be PSA derivatives which can improve the specificity and accuracy of the testing at the same time. PSA can be present in the serum in a few forms: the free from (fPSA) and forms which PSA forms stable covalent complexes with other molecules, such as alpha 1 antichymotrypsin (ACT) and alpha 2-macroglobulin (A2M), which may also be known as complexed PSA (cPSA), the sum of fPSA and cPSA adds up to form total PSA (tPSA).
The fPSA do no react with with plasma protease inhibitors therefore epitopes exposed by fPSA allow in-vitro diagnostic assessments to be developed that specifically measured either fPSA or cPSA as compared to the old PSA assays that only measured tPSA (16, 17).
In the 90s, researchers had found out that the percentage of fPSA is significantly higher in men with BPH as compared to men with prostate cancer (16). Therefore, fPSA has become a significant marker in separating the men with BPH from those with prostate cancer; however this case is not seen throughout other studies and the
In one study, Catalona and co-workers demonstrated at less than 8% of men with percentage fPSA more than 25% found out that they had prostate cancer during a biopsy. In contrast, 56% of men with percentage fPSA less than 10% had prostate cancer. In a multicenter study, fPSA was measured between the black and white men, the results demonstrated that a lower percentage of fPSA indicates a higher chance of prostate cancer and a higher percentage of fPSA indicates a low chance of prostate cancer for both of the races. Based on the results, with a cutoff of 25% of fPSA, the sensitivity of detection of prostate cancer is 95% (18). Due to these factors, the FDA approved the use of fPSA in the aid of detection of prostate cancer. However, a discrepancy occurs as a large prostate volume in patients with prostate cancer is associated with high% of fPSA, therefore patients who had long term BPH, could have false %fPSA due to the dilution effects of a large prostate (19).
Despite the findings that using %fPSA alone or in conjunction with tPSa can outperform the conventional tPSA assay as a predictor of immediate biopsy results but %fPSA might be a less useful predictor long term of prostate cancer. In the areas of %fPSA, more studies will need to be carried out.
The analysis of PSA derivatives was taken further and free PSA actually comprised of different isoforms. There are two isoforms that are intact and in an enzymatically inactive form, called i PSA and BPH-related PSA which is cleaved internally and known as B-PSA. In one study, Mikolajczyk et. al discovered that the nodular hyperplastic tissue from the transition zone of BPH patients has an increased amount of B-PSA as compared to a normal transition zone tissue (20). Another study in 2004, where Canto et al. show that the serum level of B-PSA co-related strongly to the transition zone volume rather than to the level of total PSA or free PSA. It was suggested B-PSA measurement could help in distinguishing the management of patients with BPH and not prostate cancer (21).
Another PSA isoform that was discovered to have some potential in aiding the PSA screening would be pro-PSA, which is an proenzyme precursor of PSA. Immunoassays had already been developed for the whole of 7-amino acid leader peptide, as well as the truncated forms such as (-2)pPSA, (-4)pPSA, and (-5/-7)pPSA. In comparison with the B-PSA mentioned earlier, pro-PSA appears to be at an increased amount in the serum of men with prostate cancer.
In addition in helping to increase the specificity of PSA-based screening, PSA isoforms may hep with prostate cancer aggressiveness. In a study, for men treated with radical prostatectomy, there was an increased proportion of pro-PSA that was siginificantly associated with a high Gleason grade and extracapsular tumour extension (22).
Prostate specific membrane Antigen (PSMA)
Prostate specific membrane antigen was first mentioned by Horoszewicz (23), may be an good addition to the prostate tumour marker group. PSMA is a 750 amino acid Type 2 transmembrane glycoprotein consisting of three domains which are: an intracellular, a transmembrane region and a large extracellular sequence. It is a different protein from PSA and has shown to be an effective maker for prostatic epithelium (24) and appears to be more frequently in aggressive cancer as compared to PSA. In a study, Bostwick et al (24) reported that although 70% of benign epithelium expresses the marker, PSMA was demonstrated in 78% of the prostatic intraepithelial neoplasia cells and 80% of invasive prostate cancer cells. Furthemore, in another study where patients who had undergo radical prostatectomy and were subsequent followed up, there was a increase in PSMA levels in patients whose disease showed clinical progression and a fall in the levels where patients’ disease were in remission (25).
Monitoring PSA after procedures
PSA after radical prostatectomy
A series of PSA measurements is the most effective means of detecting early recurrence of disease following radical prostatectomy. Most men have a fast decrease in the PSA levels, which are expected to be not detected within a month after the surgical procedure. If the patient is unable to reach the target of undetectable PSA levels, it indicates the presence of residual cancer cells. In a study, data from 1623 men who had a radical prostatectomy were analyzed. The 5-year recurrence free rate for the men whose initial PSA levels were more than 20ng/mL was 54%, 72% of the men with PSA levels had 10.1-20ng/mL and 82% of the men had 4.1-10ng/mL of PSA levels. The timing of PSA detection was predictive of local versus distant disease recurrence. In the first year after surgery, 7% of patients with detectable PSA had a local recurrence, but 93% of patients had distant metastases with or without local recurrence. However, after the second year, the local recurrence rates increased to 61%, whereas the distant metastases decreased to 39% (26).
In another study, it was reported that PSA doubling time was a better predictor of time to clinical recurrence than preoperative PSA, stage, and pathological Gleason score. Metastic disease was indicated after a PSA doubling of 6 months or less. Out of 77 patients, 80% of them with detectable PSA postoperatively and a doubling time longer than 6 months remained clinically disease-free, compared to 64% with a PSA doubling time shorter than 6 months (27).
Pound and co workers (26) used a doubling time of 10 months to arrive at similar conclusions. They suggested against treating patients with long PSA doubling times too early because clinical disease may go undetected for many years and most of these men could lived for many years before treatment.
PSA to monitor response to radiation therapy
There is not a definite agreement on the acceptable PSA level following radiation therapy. PSA levels will decline slowly, and a nadir may not be reached for an average of 17 months. In some patients, a transient rise in the PSA level may occur at 12 months following completion of therapy, and this usually decreases during the subsequent year. Therefore, due to these different situations occurring to patients having radiation therapy, a consensus cannot be reach.
Currently, there are two methods generally used to assess the patient prognosis. In the first method, a nadir of 0.5 ng/mL correlates with a biochemical-free survival of 5 years. According to The American Society for Therapeutic Radiology and Oncology (ASTRO) recommendation, in which a biochemical recurrence is defined as 3 consecutive rises above the nadir with measurements obtained at 3- to 6-month intervals.
With the aging population and heightened awareness of prostate cancer, and the fact that prostate cancer is a slowing growing cancer and it can go undetectable for a long period of time until the symptoms start to show, there is need to constantly improve the PSA assay or to look for other PSA derivatives to aid or replace PSA to diagnose the prostate cancer. Such derivatives would be B-PSA which is unique to BPH and pro-PSA which is increased greatly in prostate cancer can aid the clinicians in diagnosis. There is also a need to have an optimal PSA cutoff or age specific ranges which can achieve both specificity and sensitivity, and ultimately sparing the men from having unnecessary worries and prostate biopsies.
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