The clinical importance of free prostate-specific antigen (PSA)

Current Opinion in Urology

Volumn 8, Issue 5, 1998, Pages 393-399

  Stenman, Ulf Håkan ^a   Leinonen, Jari ^a   Zhang, Wan Ming ^a   Finne, Patrik ^a   Wu, Ping ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ANTICHYMOTRYPSIN; FINASTERIDE; PROSTATE SPECIFIC ANTIGEN;

BIOCHEMISTRY; BLOOD LEVEL; DIAGNOSTIC ACCURACY; EARLY DIAGNOSIS; EJACULATION; ENZYME STABILITY; HUMAN; LABORATORY DIAGNOSIS; MALE; PRIORITY JOURNAL; PROSTATE CANCER; PROSTATE DISEASE; PROSTATE HYPERTROPHY; PROSTATITIS; REFERENCE VALUE; REGRESSION ANALYSIS; REVIEW; SCREENING TEST; STANDARDIZATION; SURGICAL TECHNIQUE;

EID: 0031727152     PISSN: 09630643     EISSN: None     Source Type: Journal    
DOI: 10.1097/00042307-199809000-00006     Document Type: Review

References (70)

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15. 2-macroglobulin. This is a potential mechanism by which free PSA in serum may be lost by reaction with this inhibitor.
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19. Ravery V, Meulemans A, Boccon-Gibod L. Clearance of free and total serum PSA after prostatic surgery. Eur Urol 1998; 33:251-254. After surgery for prostate cancer and BPH, these authors observed half-lives for free PSA and total PSA of 1.4-2.3 days and 2.4-3.4 days, respectively. The values for free PSA are much higher than in other studies.
20. Mikolajczyk SD, Grauer LS, Millar LS, Hill TM, Kumar A, Rittenhouse HG, et al. A precursor form of PSA (pPSA) is a component of the free PSA in prostate cancer serum. Urology 1997; 50:710-714. The authors partially purified free PSA from serum of prostate cancer patients and showed that it contained very little if any 'nicked' PSA. Part of the PSA displayed a chromatographic behaviour similar to that of certain forms of recombinant proPSA. The authors conclude that the proenzyme form of PSA constitutes about 25% of the free PSA in prostate cancer serum. This evidence is indirect and needs to be confirmed by sequencing. The majority of free PSA behaved like mature PSA. It is surprising that this PSA did not react with plasma protease inhibitors if it is enzymatically active.
21. Noldus J, Chen Z, Stamey TA. Isolation and characterization of free form prostate specific antigen (f-PSA) in sera of men with prostate cancer. J Urol 1997; 158:1606-1609. Free PSA from serum of a prostate cancer patients with an extremely high PSA concentration was partially purified and shown to contain nicked forms of PSA by immunoblotting and sequencing. This result indicates that a substantial part of the free PSA in serum is nicked.
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23. Chen Z, Chen H, Stamey TA. Prostate specific antigen in benign prostatic hyperplasia: purification and characterization. J Urol 1997; 157:2166-2170. The authors isolated PSA from BPH nodules and showed that it mainly consists of the nicked form having little enzyme activity. The authors predict that this PSA will not form complexes with protease inhibitors when it leaks into circulation.
24. Catalona W, Hudson M, Scardino P, Richie J, Ahmann F, Flanigan R, et al. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristics curves. J Urol 1994; 152:2037-2042.
25. Catalona WJ, Smith DS, Wolfert RL, Wang TJ, Rittenhouse HG, Ratliff TL, Nadler RB. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995; 274:1214-1220.
26. Bangma CH, Rietbergen JB, Kranse R, Blijenberg BG, Petterson K, Schröder FH. The free-to-total prostate specific antigen ratio improves the specificity of prostate specific antigen in screening for prostate cancer in the general population. J Urol 1997; 157:2191-2196. This study shows that determination of the proportion of free PSA in serum can be used to improve the cancer specificity of PSA in a randomized screening population.
27. Higashihara E, Nutahara K, Kojima M, Okegawa T, Miura I, Miyata A, et al. Significance of serum free prostate specific antigen in the screening of prostate cancer. J Urol 1996; 156:1964-1968.
28. Reissigl A, Klocker H, Pointner J, Fink K, Horninger W, Ennemoser O, et al. Usefulness of the ratio free/total prostate-specific antigen in addition to total PSA levels in prostate cancer screening. Urology 1996; 48:62-66.
29. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997; 277:1452-1455. This study shows that determination of free PSA is useful for differentiation between prostate cancer and BPH at PSA concentrations below 4 μg/l. This is of importance due to the trend to lower the cut-off level in PSA-based screening of men below 65 years of age.
30. Lodding P, Aus G, Bergdahl S, Frösing R, Lilja H, Pihl CG, Hugosson J. Characteristics of screening detected prostate cancer in men 50 to 66 years old with 3 to 4 ng/ml. Prostate specific antigen. J Urol 1998; 159:899-903. This study also shows that determination of free PSA is useful at PSA concentrations below 4 μg/l.
31. Egawa S, Soh S, Ohori M, Uchida T, Gohji K, Fujii A, et al. The ratio of free to total serum prostate specific antigen and its use in differential diagnosis of prostate carcinoma in Japan. Cancer 1997; 79:90-98. This study shows that determination of the proportion of free PSA improves differentiation between prostate cancer and BPH for the PSA concentration range 2.1-10 μg/l.
32. Van Cangh P, De Nayer P, De Vischer L, Sauvage P, Tombal B, Lorge F, et al. Free to total prostate-specific antigen (PSA) ratio improves the discrimination between prostate cancer and benign prostatic hyperplasia (BPH) in the diagnostic gray zone of 1.8 to 10 ng/ml total PSA. Urology 1996; 48:67-70.
33. Gann P, Hennekens C, Stampfer M. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995; 273:289-294.
34. Harris CH, Dalkin BL, Martin E, Marx PC, Ahmann FR. Prospective longitudinal evaluation of men with initial prostate specific antigen levels of 4.0 ng/ml or less. J Urol 1997; 157:1740-1743. This is an interesting study on changes in PSA and detection of prostate cancer during follow-up of patients with a PSA value below 4 μg/l, a normal or suspicious rectal examination and a normal biopsy at initial examination. The results show that men with a PSA of less than 2.0 μg/ml have a low cancer risk within the next 3 years, but serial monitoring is beneficial in identifying high-risk cases requiring biopsy in men with an initial PSA above 2 μg/ml and especially in those whose PSA becomes greater than 4.0 μg/ml. Due to large intraindividual variation, calculation of PSA velocity did not enhance cancer detection.
35. Stein A, Barak M, Mecz Y, Rubinov R, Lurie A. Serum free/total prostatic-specific antigen in prostate cancer patients treated with LH-RH agonists. Eur Urol 1997; 32:64-68. This study shows that a favourable response to LH-RH therapy in prostate cancer is accompanied by an increasing F/T ratio whereas relapse is accompanied by a decreasing ratio. The changes in the F/T ratio correlate with changes in total PSA. The authors speculate that a high free PSA is characteristic of 'benign' prostatic disease. It will be interesting to see whether this hypothesis can be verified by characterization of free PSA from patients with various types of prostatic disease.
36. Pannek J, Rittenhouse HG, Chan DW, Epstein JI, Walsh PC, Partin AW. The use of percent free prostate specific antigen for staging clinically localized prostate cancer. J Urol 1998; 159:1238-1242. This study shows that the F/T ratio in early stage prostate cancer is significantly higher in patients with organ-confined disease than in those with locally advanced disease. A cut-off of 15% for percentage of free PSA provides a positive predictive value for organ-confined disease of 76% and a negative predictive value of 53%.
37. Arcangeli CG, Humphrey PA, Smith DS, Harmon TJ, Shepherd DL, Keetch DW, Catalona WJ. Percentage of free serum prostate-specific antigen as a predictor of pathologic features of prostate cancer in a screening population. Urology 1998; 51:558-564. This study showed that a low proportion of free PSA in serum of prostate cancer patients was associated with aggressive behaviour of the tumor, i.e. capsular penetration, high Gleason score, tumor volume, and a high percentage of tumor in the gland.
38. Bangma CH, Kranse R, Blijenberg BG, Schröder FH. The free-to-total serum prostate specific antigen ratio for staging prostate carcinoma. J Urol 1997; 157:544-547. This study confirms results from earlier studies showing that total PSA correlates with the stage of prostate cancer. It further shows that the percentage of free PSA decreases with increasing stage, but the correlation is not significant.
39. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990; 143:747-752.
40. Aihara M, Lebovitz RM, Wheeler TM, Kinner BM, Ohori M, Scardino PT. Prostate specific antigen and Gleason grade: an immunohistochemical study of prostate cancer. J Urol 1994; 151:1558-1564.
41. Tarle M, Kraljic I. Free and total serum PSA values in patients with prostatic intraepithelial neoplasia (PIN), prostate cancer and BPH. Is F/T PSA a potential probe for dormant and manifest cancer? Anticancer Res 1997; 17:1531-1534. This study shows that the proportion of free PSA is significantly lower in patients with high-grade (0.17) than in low-grade PIN (0.28), in which the proportion is similar to that in BPH (0.29). The proportion in high-grade PIN is actually similar to that in prostate cancer (0.14). If reproducible, this finding indicates that a low F/T identifies patients at risk of developing prostate cancer.
42. Jung K, Meyer A, Lein M, Rudolph B, Schnorr D, Loening SA. Ratio of free-to-total prostate specific antigen in serum cannot distinguish patients with prostate cancer from those with chronic inflammation of the prostate. J Urol 1998; 159:1595-1598. This study shows that the proportion of free PSA is similar in patients with prostatitis to that in patients with prostate cancer.
43. Ornstein DK, Smith DS, Humphrey PA, Catalona WJ. The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer. J Urol 1998; 159:1234-1237. In men without detectable prostate cancer and PSA levels of 2.6-9.9 μg/l, the proportion of free PSA in serum was positively correlated with age and prostate gland volume but was not affected by age or acute inflammation in the prostatic biopsy specimen.
44. Stenman U-H, Leinonen J, Zhang W-M. Problems in the determination of prostate specific antigen. Eur J Clin Chem Clin Biochem 1996; 34:735-740.
45. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia. Cancer 1997; 79:104-109. This study shows that the proportion of free PSA in serum is significantly higher in prostate cancer than in BPH only when prostate volume is below 40 ml.
46. Haese A, Graefen M, Noldus J, Hammerer P, Huland E, Huland H. Prostatic volume and ratio of free-to-total prostate specific antigen in patients with prostatic cancer or benign prostatic hyperplasia. J Urol 1997; 158:2188-2192. These authors studied the proportion of free PSA in relation to prostate volume in large groups of patients with BPH and prostate cancer, respectively. They concluded that the proportion is significantly lower only in prostate cancer patients with a prostate volume less than 60 ml.
47. Roehrborn CG, Gregory A, McConnell JD, Sagalowsky AI, Wians FHJ. Comparison of three assays for total serum prostate-specific antigen and percentage of free prostate-specific antigen in predicting prostate histology. Urology 1996; 48:23-32.
48. Bangma CH, Kranse R, Blijenberg BG, Schröder FH. Free and total prostate-specific antigen in a screened population. Br J Urol 1997; 79:756-762. This study demonstrates excellent correlation between three of the most commonly used assays for total and free PSA.
49. Semjonow A, Oberpenning F, Brandt B, Zechel C, Brandau W, Hertle L. Impact of free prostate-specific antigen on discordant measurement results of assays for total prostate-specific antigen. Urology 1996; 48:10-15.
50. Rodriguez-Rubio F, Robles JE, Gonzalez A, Arocena J, Sanz G, Diez CF, et al. Effect of digital rectal examination and flexible cystoscopy on free and total prostate-specific antigen, and the percentage of free prostate-specific antigen. Differences between two PSA assays. Eur Urol 1998; 33:255-260. This study shows that total PSA, free PSA and the proportion of free PSA increase 45-60 min after DRE and flexible cystoscopy. The authors conclude that serum samples for determination of PSA should be obtained before manipulation of the prostate.
51. Auvinen A, Tammela T, Stenman U-H, Uusi-Erkkilä I, Leinonen J, Schröder FH, Hakama M. Screening for prostate cancer using serum prostate-specific antigen: a randomised, population-based pilot study in Finland. Br J Cancer 1996; 74:568-572.
52. Prestigiacomo AF, Stamey TA. Physiological variation of serum prostate specific antigen in the 4.0 to 10.0 ng/ml range in male volunteers [see comments]. J Urol 1996; 155:1977-1980.
53. Nixon RG, Lilly JD, Liedtke RJ, Batjer JD. Variation of free and total prostate-specific antigen levels: the effect on the percent free/total prostate-specific antigen. Arch Pathol Lab Med 1997; 121:385-391. These authors studied the variation of serum PSA in five consecutive samples obtained over a two-week period from nine urological patients. The average coefficients of variation (CV) of free, total and percentage free/total PSA were 13.9, 7.5 and 10.6%, respectively.
54. Ornstein DK, Smith DS, Rao GS, Basler JW, Ratliff TL, Catalona WJ. Biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers [see comments]. J Urol 1997; 157:2179-2182. These authors studied the variation of PSA in three blood samples drawn two weeks apart from 84 healthy men participating in a screening study. The mean CVs for total, free and percentage free serum PSA were 15, 17 and 14%, respectively. The variation was not associated with age, total PSA and ejaculation.
55. Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology 1997; 50:239-243. This study shows that ejaculation causes an increase of free PSA in serum leading to an increase in total PSA and the proportion of free PSA after 1 h. Total PSA remains increased at 6 and 24 h, whereas free PSA decreases to baseline levels by 6 h. The mean proportion of free PSA returned to baseline by 6 h and was below baseline at 24 h.
56. Ornstein DK, Rao GS, Smith DS, Ratliff TL, Basler JW, Catalona WJ. Effect of digital rectal examination and needle biopsy on serum total and percentage of free prostate specific antigen levels. J Urol 1997; 157:195-198. The authors studied the effect of digital rectal examination and prostatic biopsy on serum PSA. One hour after rectal examination, PSA increased in about half of the men. The average increase of 0.2 μg was due to an increase in free PSA. One hour after prostatic biopsy there was a dramatic increase in free and total PSA resulting in a high F/T ratio. Total PSA remained elevated for at least one week whereas free PSA decreased rapidly, reducing F/T below the pretreatment value at 1 and 7 days.
57. Collins GN, Martin PJ, Wynn DA, Brooman PJ, O'Reilly PH. The effect of digital rectal examination, flexible cystoscopy and prostatic biopsy on free and total prostate specific antigen, and the free-to-total prostate specific antigen ratio in clinical practice. J Urol 1997; 157:1744-1747. In this study, total PSA was not significantly affected by cystoscopy, while digital rectal examination had a slight and biopsy a strong positive effect. Free PSA was increased by all these procedures, causing an increase in free-to-total PSA ratio. The rate of change in free PSA and free-to-total PSA ratio after biopsy differed between patients with benign and malignant histological findings.
58. 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 1994; 344:1594-1598.
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60. Piironen T, Pettersson K, Suonpää M, Stenman U-H, Oesterling JE, Lövgren T, Lilja H. In vitro stability of free prostate-specific antigen (PSA) and prostate-specific antigen (PSA) complexed to alpha 1-antichymotrypsin in blood samples. Urology 1996; 48:81-87.
61. Stenman U-H. Effect of long term treatment with finasteride on free and total PSA in serum [Abstract]. J Urol 1996; 155:698A.
62. Keetch DW, Andriole GL, Ratliff TL, Catalona WJ. Comparison of percent free prostate-specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin, or watchful waiting. Urology 1997; 50:901-905. As shown in earlier studies, finasteride reduces total PSA by about 50% in men with BPH without significantly affecting the proportion of free PSA. Terazosin has no effect on PSA levels. The authors suggest that the proportion of free PSA could be used to screen for prostate cancer in men taking finasteride.
63. Pannek J, Marks LS, Pearson JD, Rittenhouse HG, Chan DW, Shery ED, et al. Influence of finasteride on free and total serum prostate specific antigen levels in men with benign prostatic hyperplasia. J Urol 1998; 159:449-453. These authors also found a 50% decrease in total PSA during finasteride therapy and no significant change in the proportion of free PSA.
64. Kalish J, Cooner WH, Graham SJ. Serum PSA adjusted for volume of transition zone (PSAT) is more accurate than PSA adjusted for total gland volume (PSAD) in detecting adenocarcinoma of the prostate. Urology 1994; 43: 601-606.
65. Zlotta AR, Djavan B, Marberger M, Schulman CC. Prostate specific antigen density of the transition zone: a new effective parameter for prostate cancer prediction [see comments]. J Urol 1997; 157:1315-1321. This study confirms the results from earlier studies [64] showing that PSA density of the transition zone is more accurate in predicting prostate cancer than total prostate PSA density at PSA levels below 10 μg/l.
66. Pearson JD, Luderer AA, Metter EJ, Partin AW, Chan DW, Fozard JL, Carter HB. Longitudinal analysis of serial measurements of free and total PSA among men with and without prostatic cancer. Urology 1996; 48:4-9.
67. Finne P, Zhang W-M, Leinonen J, Stenman U-H. The diagnostic accuracy of PSA determinations by logistic regression analysis [Abstract]. Scand J Clin Lab Invest 1998; 58 (Suppl 228):105-106. The authors used logistic regression analysis of free and total PSA to estimate the probability of finding prostate cancer by biopsy in men participating in a screening study. The combination of an F/T below 0.10 and a total PSA of 4 μg/l was associated with a higher cancer probability than a total PSA of 30 μg/l and an F/T of 0.30. Thus men with a total PSA below 4 μg/l and a low F/T have a higher probability of cancer than many of those with a PSA above 10 μg/l. This shows that fixed cut-off values of 4 and 10 μg/l are arbitrary and that valid statistical methods should be used to estimate cancer probability based on free and total PSA over a wide range of total PSA values.
68. Woodrum DL, Brawer MK, Partin AW, Catalona WJ, Southwick PC. Interpretation of free prostate specific antigen clinical research studies for the detection of prostate cancer. J Urol 1998; 159:5-12. The authors emphasize that statistically valid multi-site clinical trials that take into account influencing factors should be performed to establish assay-specific cut-off points for free and total PSA associated with a certain probability for prostate cancer.
69. Marley GM, Miller MC, Kattan MW, Zhao G, Patton KP, Vessella RL, et al. Free and complexed prostate-specific antigen serum ratios to predict probability of primary prostate cancer and benign prostatic hyperplasia. Urology 1996;16-22.
70. Gomari M, Järvi T, Hugosson J, Finne P, Stenman U-H. Learning vector quantization, multilayer perceptron, neurofuzzy network and logistic regression in the diagnosis of prostate cancer. In Arabnia H (ed.), Proceedings of the 1998 International Conference on Parallel and Distributed Processing Techniques and Applications (PDPTA). Las Vegas: CSREA Press, 1998; Vol. 1. pp. 516-525. The authors compare four different methods of improving the diagnostic accuracy for prostate cancer using age, the results of free and total PSA determinations, digital rectal examination and transrectal ultrasound as input variables in a screening population comprising men aged 50-65 years. Of the variables, free and total PSA and digital rectal examination provide independent information. Learning vector quantification gives significantly better discrimination than the other methods. The results suggest that risk calculation by modern computing techniques may significantly improve the diagnostic accuracy for prostate cancer, especially when several input variables are used.