PSA as a marker for prostate cancer: a critical review

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1 Review Article Ann C/in Biochem 1996; 33: PSA as a marker for prostate cancer: a critical review M J Duffy From the Department of Nuclear Medicine, St Vincent's Hospital, Dublin 4, Ireland Additional key phrases: PSA-inhibitor complexes; screening; monitoring; staging Prostate-specific antigen was first identified by Hara et al. in and given the name y seminoprotein. In 1978, Sensabaugh and Crim? purified the protein from seminal plasma and characterized it as a potential semen marker with applications in forensic science. In 1979, Wang et al. 3 purified the protein from prostate tissue. Since it was found in all types of prostatic tissue but not in any other human tissue it was given the name prostate-specific antigen (PSA). THEPSA GENE The PSA gene contains five exons and four introns." In humans, it is located on chromosome 19 and spans a region of DNA approximately 6 kb in length. The PSA gene is approximately 80% homologous with the gene for glandular kallikrein. A number of different mrna molecules are transcribed from the PSA gene." One transcript, 1 6 kb in length, contains all the gene exons and is translated into the 33 kda PSA protein. Other transcripts apparently due to aberrant splicing have also been found. Preliminary findings suggest that different splice variants are produced in benign prostatic hyperplasia (BPH) and cancer.! THE PSA PROTEIN PSA is a protease with a molecular weight of kda (reviewed in references 4 and 6). The molecule consists of approximately 92% peptide and 8% carbohydrate.v" PSA exists in at least five isomers with isoelectric points (PI) ranging from 6 8 to 7 5. The pi of the major isoform is 6,9. 6 The different isomers do not appear to be encoded by different genes but seem to result from different sialic acid content. Like other proteases, PSA in serum consists mostly of complexes with inhibitors." The predominant complex is with IXI-antichymotryp- Correspondence: Dr M J Duffy. sin (ACT). Smaller amounts of PSA are also bound with lxi-proteinase inhibitor, 1X2-macroglobulin and inter-a-trypsin inhibitor. A minor amount of PSA also exists in the free form," but whether this free form is biologically active remains to be determined. It is also unclear whether all the PSA isoforms bind to inhibitors with similar affinity or if the free PSA relates to a specific isoform. Most of the commonly available immunoassay kits for PSA appear to detect both free PSA and the ACI complex," The sum of both fractions contribute to the 'total PSA' concentration in serum. Depending on the antibody reactivity of the various assays, the total PSA detected will depend on whether the free PSA and complexed PSA are determined on an equimolar basis. The data presently available suggest that few of the commercially available kits detect free and complexed PSA in an equimolar equivalence pattem.! At a recent Consensus Workshop on Screening and Global Strategy for Prostate Cancer.s it was concluded that the most accurate PSA assay would be one in which both free and complexed form were detected on a equimolar basis. However, the committee also recommended that the long-term goal should be the establishment of an international PSA standard preparation. The Hybritech Tandem-R assay was accepted as a 'provisional' reference method by this workshop," BIOLOGICAL FUNCTION OF PSA As a serine protease, PSA can catalyse the hydrolysis of a number of protein substrates. Originally, the main physiological function of PSA was thought to be liquefaction of seminal coagulum." However, PSA has also been found to catalyse the hydrolysis of other substrates such as insulin-like growth-factor binding protein-3 (IGFBP-3).IO IGFBP-3 is one of a number of serum binding proteins for insulin-like growth factors (IGF) I and II. The latter are growth factors for a variety ofdifferent cells. Thus, PSA mediated hydrolysis of IGFBP-3 may modulate the levels of IGFs and consequently rates of 511

2 512 Duffy cellular proliferation. Recently, PSA was shown to catalyse degradation of the extracellular matrix proteins fibronectin and laminin. II Furthermore, inhibition of PSA proteolytic activity using antibodies against the protease resulted in decreased invasion of an artificial basement membrane by prostate carcinoma cells. 1 I These findings suggest that PSA, like certain other proteases.f may play a role in cancer invasion and metastasis. PSA IS NOT A PROSTATE-SPECIFIC MOLECULE For many years, PSA was thought to be synthesized specifically by prostate epithelial cells. Recent work, however, has shown that PSA can be present in other organs (e.g. sweat, periurethral and anal glands, endometrium and breast), in non-prostate tumours (e.g. breast and salivary glands) and in certain fluids (e.g. milk and amniotic fluid).13-1s In these fluids, most of the PSA is in the free form with less than 25% complexed with ACT.14,lS This is in contrast to blood where most of the molecule is bound to inhibitors, especially to ACT, see above. The finding of PSA in organs other than the prostate may have implications when using PSA as a marker for prostate cancer. For example, in metastatic cancer with an unknown primary, positive staining for PSA is widely used in establishing the prostate as the primary site. If PSA is also synthesized by non-prostatic cancer, a prostatic origin, based on the presence of PSA, cannot be relied upon. Furthermore, up until now, all PSA in sera was thought to be derived from prostatic tissue. Ifother normal tissues and non-prostatic malignancies also synthesize PSA, the possibility exists that serum PSA may not exclusively originate from prostatic tissue. Present indications, however, are that non-prostatic sources of PSA do not affect the use of this molecule as a marker for prostatic cancer.p USE OF PSA IN SCREENING FOR PROSTATIC CANCER In many Western countries, prostate cancer is the second most common malignancy in men. In the USA, it has now surpassed lung cancer in terms of absolute incidence. In the European Union, 13% of malignancies diagnosed in men are prostate cancers and 8 6% of all cancer deaths are due to this disease.l" One potential approach to reducing the mortality from prostate malignancy is to screen asymptomatic men for early disease. Using this approach, prostate cancer could be detected when it is confined to the prostate and therefore potentially curable. Recently, the American Cancer Society recommended that annual digital rectal examination (DRE) and serum PSA assay be carried out on all men aged 50 years or older. The use of PSA as a screening test for prostatic cancer is now discussed. If PSA or any other test is to be used in screening, a number of criteria must be met.!? (a) the test should be safe and cheap so that it will have wide acceptance (b) the disease being detected is serious and common in the population under study (c) an effective treatment is available that results in decreased morbidity and mortality in the screened population (d) the test must have high sensitivity and specificity, a low false negative and false positive rate as well as a high negative and positive predictive value. The currently available modalities for the early detection of prostate cancer are digital rectal examination, transrectal ultrasonography (TRUS) and PSA. The advantages and disadvantages of each of these tests are now briefly discussed. DRE DRE is relatively simple and fast. However, it is subjective, relatively expensive when performed by qualified medical staff and lacks sensitivity for early prostate cancers. Moreover, it is not a well accepted test by certain populations. TRUS In some but not all studies TRUS has been found to be more sensitive than DRE. 18,19 It is also relatively simple and fast in experienced hands. However, as pointed out by Kojima and Babaian19 it has a low positive predictive value (approximately 30%) and is relatively expensive. TRUS is usually reserved for the evaluation of patients with either abnormal DRE or PSA. PSA As a screening test for prostate cancer, PSA is superior to both DRE and TRUS because of its objectivity and cost-effectiveness. 19 Furthermore, in contrast to DRE, it is widely acceptable. In recent years a number of studies have evaluated the value of PSA as the initial test for early detection of prostate carcinoma.

3 PSA as a marker for prostate cancer 513 Catalona et al. 20 measured PSA in 1653 asymptomatic men 50 years and older. Thirtyseven patients with cancer were found during the screening process. In this study, 12/37 cancers would have been missed if DRE alone had been used and 16 if only TRUS was used. More recently, these authors" showed that screening with PSA led to the detection of significantly more organ-confined prostate cancers than did DRE. It can be concluded from these and other studies (reviewed in reference 22) that the use of PSA can detect more prostatic cancers than can DRE and that more of these cancers are localized and, thus, potentially curable. The use ofpsa may also provide a substantial lead time in the diagnosis of clinically significant prostatic cancer. Tibblin et al.,23 using stored sera, found that a PSA greater than 4 ng/ml, (Hybritech Tandem-R assay) was associated with at least a 20-fold increased risk of developing cancer within 11 years. The mean lead time for diagnosis from the time of blood sampling was 6 7 years. In another study using archival plasma, Gann et al. 24 showed that the mean lead time provided by PSA was 5 5 years. In this study, baseline PSA concentrations correctly identified 87% of all aggressive prostate cancers found within the first 4 years. These diagnostic lead times provided by PSA are significantly longer than the approximately 3 years usually found with mammographic screening for breast cancer." Although PSA is superior to DRE for the early detection of prostatic cancer, it has two main disadvantages as a screening test for this malignancy. First, elevated serum concentrations of this molecule are not specific for prostate cancer. Non-malignant diseases such as BPH, acute prostatitis, prostatic ischaemia and infarction can all cause elevated PSA concentrations in blood.f Approximately 25 30% of patients with BPH have a serum PSA concentration above the commonly used reference range of Q-4 ng/ml, (Hybritech Tandem-R PSA assayj." The second main disadvantage of PSA in screening for cancer is that approximately 30 45% of patients with organ-confined prostate cancer have a PSA within the reference range.f Using PSA alone, these men would not be identified. A number of studies have compared PSA concentrations in patients with BPH and with localized or organ-confined cancer. In one such study, Partin et al. 26 found that the mean PSA concentration for BPH patients was 5 9 ng/ ml and 5 6 ngjml for patients with cancer. In another study, median PSA concentrations for BPH and cancer patients were 4 0 and 5 9 ngj ml, respectively.f In this study, while levels were significantly higher in cancer patients than in the control group, considerable overlap in values was found. Clearly, PSA alone lacks sensitivity and specificity for the early diagnosis of prostate cancer. Because of these limitations a number of different approaches have been used in an attempt to enhance the ability of PSA to differentiate prostate cancer from BPH. These approaches include: (a) measurement of PSA density; (b) longitudinal measurements of PSA; (c) use of age-related reference ranges; and (d) measurement of both free and complexed PSA in addition to total PSA. PSA density PSA density (PSAD) is the serum PSA value divided by the prostate volume, the latter being obtained by ultrasonography. The rationale for calculating this index is that malignant prostate tissue synthesizes a greater amount ofpsa per gramme of tissue than does benign prostate. Thus, Stamey et al. 2M calculated that prostate cancer contributes 3 5 ngjml, per ml oftissue to serum whereas BPH supplies only O'3 ngjml per ml of tissue (data based on Yang, Pros-Check assay). Benson et al. 29 were one of the first groups to show that PSAD was better than PSA alone in differentiating malignant from benign prostate disease. These workers found that the mean PSAD was for BPH and for prostate cancer. In patients with cancer, only two had a PSAD of less than 0 03 while none of the patients with BPH had a density greater than From this data, Benson et al. 29,30 concluded that a PSAD greater than 0 15 was abnormal. PSAD was found to be superior to PSA especially in patients with serum PSA values between 4 1 and 10 ngjml. While these original results of Benson et al. 29 have been confirmed by some;" others 32,33 found no significant difference between PSA and PSAD in differentiating prostate cancer from BPH. These conflicting results are probably due to difficulties in determining prostate volume rather than in the PSA assay. As pointed out by Benson et al.,30 measurement of prostate volume cannot be made retrospectively unless the transrectal ultrasonography of the prostate was performed diligently. Another problem with Ann cu«biochem 1996: 33

4 514 Duffy PSA density is that the epithelial-stromal ratio varies considerably from one prostate tumour to another and only the epithelial cells synthesize PSA. Thus, two prostate cancers of similar size could produce different amounts of PSA depending on the proportion of epithelial cells present. Serial measurements of PSA A different approach to increasing the specificity ofpsa for prostate cancer has been to use serial assays. Carter et al. 34 showed that, while PSA values measured 5 years before diagnosis did not differentiate BPH from prostate carcinoma, the rate of change in PSA levels was significantly greater in subjects with the cancer compared with control subjects and men with BPH. In patients who developed prostate malignancy, PSA levels increased exponentially 5-10 years before diagnosis. On the other hand, in the control group, changes in PSA concentration over time were not significantly different from zero while changes in the BPH group were described as 'gradual'. In this study, the rate of change in PSA levels differentiated patients with prostate cancer from patients with BPH and control subjects with a specificity of 90% and 100%, respectively. One criticism of this study is that the sample size was small, with only 18 patients developing prostate cancer. Furthermore, PSA was assayed on stored sera and not on serial samples collected over many years, as would be the likely situation in routine practice. In the later situation, interassay imprecision would be greater than with stored specimens and this could decrease the specificity of the serial measurements. It is of note that Catalona et al. 35 were unable to confirm the above findings in a prospective study while Riehmann et al. 36 found increases in serum PSA levels in consecutive samples from 13% of 129 men with no apparent malignancy. Clearly, before serial determinations of PSA can be used in prostate cancer screening, assays with high precision within the reference range will have to be available. As pointed out by WU,37 the precision and accuracy of tumour marker assays within the normal range has not in the past been given a high priority. On the other hand, if stored samples are to be used, the long-term stability of this molecule must be checked and optimum storage conditions established. Use of age-adjusted reference range Another possible way to enhance the ability of PSA to distinguish BPH from prostate cancer is the use of age-specific reference ranges. Oesterling et al. 38 were one of the first groups to show that median serum PSA values increased with each decade of life in men who were apparently free of prostate cancer. Using regression analysis, PSA levels were found to increase by 3 2% per year or by 0 04 ng/ml, per year for a 60 year-old man. Oesterling et al. 38 concluded that if serum PSA levels vary with patient age, so should the reference range. They also suggested that while the widely used reference range of0 4 ng/rnl, may be appropriate for 60-year-old men, this range may not be suitable for younger or older subjects. Based on their data, Oesterling et al. 38 suggested the following age-related reference ranges for white American men: ng/ml, for men years, ng/ml, for men 50-59, ng(ml for men and ng(ml for men aged years. It should be stated that these ranges apply to both the Hybritech Tandem-R and Abbott IMx assays. More recently age-specific reference ranges were calculated for Japanese men and these were shown to be lower than for the white American population.i? Because ofthese racial differences, age-specific reference ranges should now be established for other ethnic groups. Lankford et al. 4D investigated the use of using age-specific reference ranges on the sensitivity and specificity of PSA in detecting prostate cancer in over men. These authors conclude that for men over 70 years of age, the age-specific reference range led to increased specificity compared with the unadjusted reference range. However, sensitivity was decreased. There was no significant difference in either sensitivity or specificity for subjects less than 70 years of age." Measurement of free and PSA complexes As previously discussed, the major form of PSA in serum is as a complex with ACT. Recently, patients with prostate cancer were reported to have a higher proportion of the PSA-ACT complex than those with BPH.4! Furthermore, preliminary data suggests that the ratio of PSA ACT complex to total PSA allows better discrimination between patients with prostate cancer and those with benign disease." Using this ratio it was shown that the frequency of

5 PSA as a marker for prostate cancer 515 false positive results can be reduced by approximately 50%.42 While the PSA-ACT to total PSA ratio is lower in controls than in cancer patients, the free PSA/total PSA ratio is higher in the control group than in patients with malignancy. Measurement of the free/total PSA ratio has also been shown' to be superior to total PSA in discriminating between BPH and prostate cancer. In one study using a sensitivity setting of 70%, specificity increased from 46% with total PSA to 71-73% with the free/total ratio." It should be stated that these results were obtained from patients presenting with total PSA values of 1-20 ng/rnl.. The proportion of free to total PSA in blood may depend on the size of the prostate gland. Thus, Catalona et a/. 44 have shown that the median percentage of free PSA was 9 2% in patients with cancer and a normal-sized gland, 15 9% in patients with cancer and an enlarged gland and 18 8% in men with BPH. In this study, the free PSA percentage showed no correlation with Gleason grade (a commonly used grading system for prostatic carcinomasv) and was unable to differentiate early from advanced cancer. However, in patients with an enlarged, palpably benign gland, a free PSA cutoff of 23-4% or lower detected at least 90% of the cancers and would have eliminated 31 3% of negative biopsies.f The above preliminary studies suggest that the ratio of either free PSA or PSA/ACT complex to total PSA is superior to total PSA in the diagnosis of at least some subgroups of patients with prostatic cancer. Because of the ease of calibration and the accuracy of the free PSA assay relative to that of the PSA/ACT complex, Pettersson et a/.% have argued that measurement of the free to total PSA more reliably indicates the inverse of the proportion of PSA complexed to ACT in blood. If free PSA measurement enters routine use, its assays (like that for total PSA) will have to be standardized and a strategy established for the optimum combination of free with the total fraction. Is screening for prostatic cancer justified? Before concluding this section on the potential value of PSA in detecting early prostate cancer, it is important to mention that screening for this disease is still controversial. Unlike screening for cervical and breast cancers, there is little evidence currently available that the early detection of prostatic malignancies can extend overall survival. We must therefore ask whether screening for prostate cancer with present methodologies is justified. Using DRE, Gerber et al. 47 concluded that screening had no significant impact on long-term patient outcome. However, as mentioned above, DRE is an insensitive test for prostate cancer screening and inferior to PSA. Using mathematical modelling, Krahn et a/. 48 showed that the benefits of decreased deaths from prostate cancer are negated by the morbidity of the cancer treatment. These authors also predicted that screening for this disease will result in net harm rather than in a net health improvement. They furthermore stated 'that in any screening program, many men will be given a diagnosis of cancer which would otherwise have lived out their full lifespan without knowing of or suffering any of the complications of their cancer'. With regard to this latter point, it is known that 30-40% ofmen older than 50 years of age have histological evidence of prostate cancer as revealed in autopsy studies. 19 However, the number of clinically diagnosed prostate cancers is considerably lower than the number detected at autopsy. Thus, Scardino has estimated that only one in 95 men with prostate cancer have a clinical diagnosis of their disease and only one in 323 die of the disease." This major discrepancy between the pathological incidence and clinical prevalence of prostate cancer is one of the main arguments against screening for prostate malignancy. It is important to point out that the study of Krahn et a/. 48 has been criticized, as the patients used for their calculations tended to be old and not representative of those seen in a general urological practice. 50 Another argument against prostate screening is the high cost. Optenberg and Thompson" have calculated that the costs for the screening and treatment of all men years old in the USA would be approximately 28 billion dollars in the first year. This expenditure would require that the proportion of the USA health budget allocated to prostate cancer rises from 0 06% to greater than 5%. In theory, the screening program would detect over 1 6 million subjects with prostate cancer (using 4 ng/ml, as cut-off point for PSA). However, the screening would result in impotent men, with incontinence and requiring a colostomy. In addition, there would be treatmentrelated deaths. Finally, no evidence was

6 516 Duffy presented that screening would decrease the death rate from prostate cancer.>' Most of the literature relating to the value of PSA in screening has focused on un selected male populations older than 50 years. In contrast, few studies have addressed the issue of screening high risk subjects. Criteria that can be used to identify men at above average risk of developing prostate cancer include age, ethnicity, country of origin and family history of the disease. It is of interest that in one recent study the positive predictive value of a PSA concentration greater than 3 ng/ml, (as determined by the Hybritech Tandem-R assay) was greater in men with a family history of prostate cancer than amongst those without affected first degree relatives.p However, the higher predictive value associated with a positive family history was confined to men with a normal DRE. USE OF PSA IN STAGING PROSTATIC CANCER Staging defines the extent of tumour growth and progression at a particular point in time. For most cancers, two staging systems exist, clinical and pathological. Clinical staging is based on physical examination, laboratory tests and radiological procedures while the pathological approach uses biopsies to determine the degree of spread, and involvement of lymph nodes. Pathological staging is more reliable than clinical staging but requires invasive procedures such as surgery. For patients presenting with prostatic cancer it is desirable to have a noninvasive preoperative test to assess the extent of disease spread and thus make a rational decision on the most appropriate type of surgery or other treatments. As serum PSA values tend to increase with increasing stage, it has the potential to aid disease staging. However, as previously pointed out, there is considerable overlap in values between different stages. 6,22 PSA alone is thus not sufficiently reliable to determine stage on an individual basis. In particular, PSA concentrations are unable to differentiate patients with organ-confined cancer from those with extracapsular disease. While serum PSA values are of little use in detecting capsular penetration, preliminary data suggest that it may be a predictor of pelvic lymph node metastases.p This predictive ability of PSA can be further enhanced by combination with Gleason grade and local clinical stage. These findings, if confirmed, should lead to a reduction in open or laparoscopic staging bilateral pelvic lymphadenectorny.p Finally, PSA is an excellent prediction of bone metastasis in patients with prostatic cancer. In subjects with newly diagnosed disease without skeletal symptoms and a PSA value less than 10 ng/ml., bone secondaries are unlikely to be detected by radionuclide scanning.p In this situation, Oesterling-l has suggested that staging bone scans are unnecessary. Thus, the assay of PSA has the potential to reduce both the numbers of staging bilateral pelvic lymph node dissections and isotope bone scans, resulting in significant cost saving. Recent findings suggest that measurement of mrna for PSA in blood cells may be more sensitive than PSA protein in the preoperative staging of prostatic cancer. In preliminary studies, Katz et al. 53 have shown that the use of enhanced reverse transcriptase-polyrnerase chain reaction (RT-PCR) for PSA mrna was more sensitive for detecting extra-prostatic disease than serum PSA, digital examination or imaging. Furthermore, RT-PCR for PSA mrna has been used to detect micrornetastasis from primary prostate cancers in both lymph nodes and bone marrow However, it is not known if the presence of PSA-containing cells at these sites can be equated with metastasis. Solid cancers are known to release malignant cells into the circulation at an early stage in their growth, yet few of these cells appear to form distant metastases. 56 Furthermore, the presence ofthese cells in distant organs, such as the bone marrow, may reflect circulatory blood obtained with the sample rather than micrornetastasis." Prospective long-term follow-up of these patients will be required to determine the clinical significance, if any, of these PSA-containing cells distant from the prostate. USE OF PSA IN MONITORING PATIENTS WITH DIAGNOSED PROSTATIC CANCER Presently, the main clinical application ofpsa is in monitoring patients with diagnosed prostate cancer. For the follow-up of these patients PSA is now the marker of choice, being more sensitive than total acid phosphatase, prostatic acid phosphatase and bone alkaline phosphatase (for review, see reference 6). During patient follow-up, serial PSA levels can be used for a number of different purposes.

7 PSA as a marker for prostate cancer 517 First, PSA can be used to monitor the success of radical prostatectomy in removing all prostate cancer. In early studies, Stamey et al. 28 showed that after radical prostatectomy, PSA fell to undetectable levels with a half-life of 2 2 days. From these findings, Stamey et al. 28 concluded that the presence of detectable PSA in blood 3 weeks after radical surgery denoted the presence of residual cancer. This conclusion may now have to be modified to take into consideration both the recent findings on PSA in non-prostatic tissues (see above) and the development of more sensitive assays for this rnarker.? Irrespective of the origin of PSA in blood, measurement of its levels post-radical prostatectomy appears to provide prognostic information. Thus, Lange et al. 58 have shown that patients with a PSA concentration lower than 0 4 ngjml, 3-6 months after radical surgery were less likely to develop recurrent disease than those with a value greater than 0 4 ngjml. Frazier et al.,59 however, recently questioned the clinical value of using serial PSA measurements to evaluate outcome after radical prostatectomy. These authors found that the incidence of clinical failure was less than the number of patients with PSA elevations. They therefore concluded that apparent biochemical failure may not translate into disease-initiated death in the lifetime of the patient. Clearly, a study is necessary to compare survival and quality oflife in patients treated by prostatectomy and followup with and without serial PSA determinations. Changes in PSA levels after radiation therapy are less clear than after radical prostatectomy. In patients who respond, PSA concentrations fall but can take up to a year to reach their lowest levels. The mean PSA half-life after radiation therapy is approximately 2 months with a range from 0 5 to 92 months.t" Conflicting results exist on whether the rate of fall of PSA following radiation therapy is of prognostic value.r" PSA can also be used in the follow-up of patients managed by surveillance only. Since PSA is proportional to prostate cancer volume, serial PSA measurements in the absence of any treatment should reflect tumour growth rate or doubling time." It is important to note, however, that tumour doubling times can be overestimated in patients with a large volume of BPH as the hyperplasia also contributes to PSA concentrations in serum. Schmid''' has therefore recommended that when following the doubling time of prostate cancer using serial levels, an estimate of prostate volume should be available. Finally, PSA can be used to follow the treatment of advanced prostatic cancer, e.g. by anti-androgens. In a number of studies of this type, pretreatment PSA concentrations have been shown to be inversely proportional to survival. For example, Matzkin et al. 62 showed that for patients with advanced disease (Stage D2), progression-free survival was longer than 36 months for patients with pretreatment concentrations 0-99 ng/ml., 12 7 months for those with PSA concentrations ngjml and 7 4 months when the PSA concentration was greater than 500 ngjml. In these studies, PSA was measured with the Hybritech Tandem R assay. Caution, however, may be necessary in interpreting PSA values following hormonal therapy. As the synthesis of this marker is increased by androgens," a portion ofthe decline after androgen ablation treatment may be due to diminished expression rather than tumour regression.v' CONCLUSION PSA is presently the best biochemical marker available for prostate cancer. High concentrations of PSA in serum have the potential to diagnose clinically significant prostate cancer at an early and potentially curable stage.p Furthermore, in many patients, elevated serum concentrations may be the only indication of malignant disease. However, the recommendation that DRE and PSA should be used in screening for early prostate cancer is not based on hard scientific data. So far there are no studies showing that screening leads to prolonged survival of patients with prostate cancer. Until results are available which show that the early detection of prostate malignancy leads to enhanced survival, mass screening cannot be advocated. Finally, PSA can aid prostate cancer staging and is superior to acid phosphatase or any other available marker in the follow-up of patients with diagnosed prostate cancer. REFERENCES Hara H, Koyangagi Y, Inoue T, Fukuyama T. Some physiochemical characteristics of gamma-seminoprotein: an antigenic component specific for human seminal plasma. Jpn J Legal Med 1971; 25: Sensabaugh GF, Crim D. Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification. J Forensic Sci 1978; 23:

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