Interpretation of "Ultransitive" Prostate Specific Antigen (PSA) Test Results: How Low
do we Want to Measure?
PD Dr. med. Axel Semjonow (e-mail: Semjono@uni-muenster.de), Prostatazentrum am Universitätsklinikum
Münster und Gabriela De Angelis, Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Albert-Schweitzer-Straße 33, 48149 Münster, GERMANY
Prostate specific antigen (PSA) is one of the best tumor markers available today [8]. As PSA has a high specificity for prostate tissue but not for prostate cancer tissue, PSA cannot reliably distinguish between benign and malignant prostate tissue. PSA is produced almost only in the prostate so it should no longer be detectable in rum a few weeks after complete removal of the prostate by radical prostatectomy. It is therefore of greatest informative value after surgical removal of the prostate as measurable PSA concentrations after surgery indicate that detection of residual tumor or tumor recurrence is likely while rapidly rising concentrations confirm this diagnosis. PSA is prent in rum in complexed and in free forms, both forms together constitute the total PSA (t-PSA) (Chapter 6). In the diagnostic workup the parate determination of the different forms of PSA permits better differentiation
between benign prostatic hyperplasia and prostate cancer. For the purpo of monitoring after treatment, however, only determination of total t-PSA is appropriate [34].
The half-life of t-PSA in the blood is about 1.5 days [37], that of f-PSA only a few hours [3, 27] so that t-PSA concentrations of around 0.1 µg/l in the blood are reached about three to four weeks after radical prostatectomy [38]. The detection of higher t-PSA concentrations in the rum of men after radical prostatectomy suggests the persistence of prostate tissue, rising t-PSA levels after radical prostatectomy are considered reliable evidence of residual tumor. Recurrence of prostate cancer without measurable t-PSA concentrations has not been obrved [25] or is a rarity [23]. Therefore the u of imaging procedures for follow-up after radical prostatectomy in patients with undetectably low t-PSA concentrations is not clinically relevant.
Definition of "Ultransitive" t-PSA Assays
There is no generally accepted definition of "ultransitive" t-PSA assays. While in the past assays with a lower detection limit of 0.2 µg/l were described as "hypernsitive" [2], today the terms "ultra-", "super-" or "hyper-" nsitive usually refer to assays with a lower detection limit below 0.1 µg/l. Many commercially available assays reach this concentration [35] some go even lower [31, 45]. New meas
uring technologies still in the developmental stage will be able to increa the precision of PSA assays in very low concentration ranges [21, 40].
Determination of the Lower Limit of Detection
There is no generally accepted procedure for determining the biologically relevant lower limit of detection for t-PSA assays for monitoring after radical prostatectomy [41]. In the abnce of a generally accepted method the manufacturers of most t-PSA assays usually give the "analytical" lower detection limit, determined as the mean of multiple measurements of the 0-calibrator plus two or three standard deviations. As this procedure rules out interference by rum components the "analytical" lower limit of detection usually is lower than the "functional" lower limit of detection but it may not be meaningfully ud for clinical decisions. For patients after radical prostatectomy determination of the "functional" lower limit of detection, obtained by dilution of ra with very low t-PSA concentrations and determination of the concentration at which the coefficient of variation exceeds 20% or the dilution linearity disappears, is of greater clinical relevance [15]. For the clinical evaluation of a possible “PSA recurrence” the lower limit of detection given by the manufacturer of the assay should not be ud unconditionally [7].
iroInterference by t-PSA of Extraprostatic Origin in "Ultransitive" Assays While the lower limit of detection of the first t-PSA assays was around 0.5 µg/l [24], today’s commercially available assays usually reach concentrations of 0.1 µg/l or lower [36, 45]. Modifications of the assays, so-called "ultransitive" assays, make it possible to detect far lower t-PSA concentrations and there is a risk that even extremely small amounts of t-PSA produced by extraprostatic tissue or in female ra may be detected [1, 5, 6, 9, 12, 14, 16, 17, 20, 22, 26, 29, 48].
The detection of such low t-PSA concentrations in the rum of men after radical prostatectomy leads to interpretation problems as a minimal amount of residual benign prostate tissue or PSA from periurethral glands may be enough to produce measurable t-PSA concentrations without there necessarily being any residual tumor prent [28].
The assays are also able to detect t-PSA in the rum of some women [10, 49]. Moreover, the precision of
immunological assays is lowest clo to the lower limit of detection (= high coefficient of variation), so that repeated measurements in the same sample can produce markedly discrepant results (Fig. 7.1) [4, 39]. It is also possible that other molecules from the kallikrein family that remble PSA may l
ead to fally high results due to cross reactivity [15, 33]. Fig. 1: The coefficient of variation (CV [%]) as measure of the variation of results from veral measurements in the same sample in relation to the arithmetic mean (= standard deviation x 100 / arithmetic mean) is greater near the lower detection limit of an immunological assay than near the upper limit of the measuring range.
Earlier Detection of Residual Cancer with Ultransitive Assays
With ultransitive assays a “PSA recurrence” can be diagnod considerably earlier than with conventional assays. Most studies show a lead time of about one year compared with conventional assays [11, 19, 30, 32, 44] (Fig. 7.2, 7.3). In some studies there was a correlation between detection of “ultransitive” t-PSA concentrations after radical prostatectomy and the prence of unfavorable histopathological parameters.
Fig. 7.2:
Ultransitive assays for t-PSA (lower limit of
detection < 0.1 µg/l) permit the detection of
residual cancer after radical prostatectomy about
one year before conventional assays (lower limit
of detection ≥ 0.1 µg/l). In about one third of the
patients PSA increas in ultransitive assays
are not confirmed by PSA increas in
conventional assays.
新东方优能Fig. 7.3: In about one third of patients "ultransitive" PSA assays detect measurable PSA concentrations after radical prostatectomy which are not confirmed in the further cour by PSA increas in conventional assays as indication of residual cancer. If the PSA increa is confirmed by conventional assays the "ultransitive" procedure detects the residual cancer about one year earlier.
VC {%] t-PSA (µg/L) 0 20 40 60 80
100 0
4
16
8
12
爱问 共享资料
20
udid0,0
0,10,20,3051015202530
Months after radical prostatectomy t -P S A [µg /l
]0,0
0,1
0,20,3
天津环球雅思0510********
Months after radical prostatectomy t -P S A [µg /l ]
PSA Fluctuations in the Very Low Concentration Range
zoom怎么读In most studies it remains unclear how often "ultransitive" detection of t-PSA is not confirmed in the further cour by measurement of increasing values in conventional assays. However, studies which describe the percentage of such fal-positive t-PSA increas in ultransitive assays suggest that this is a relatively common occurrence in assays with a lower detection limit below 0.1 µg/l. At a lower detection limit of 0.06 µg/l Takayama et al. [42, 43] found measurable t-PSA concentrations which were not confirmed in the further cour by the conventional t-PSA assay in 20% of the patients. Witherspoon [46, 47] describes 33% nonconfirmed increas at a lower detection limit of 0.01 µg/l, Ellis et al. [13] found 38% non-confirmed increas at a lower limit of detection of 0.03 µg/l. In the largest study to date, conducted in 422 patients after radical prostatectomy, Hae et al. [18] found that t-PSA concentrations detected with an assay with a lower limit of detection of 0.025 µg/l were not confirmed by conventional methods within the time frame of the study in 26% of the patients.
Clinical Conquences of Very Low t-PSA Concentrations After Radical Prostatectomy?
There are no studies to date which have examined whether the "ultransitive" detection of PSA, by
triggering early u of adjuvant treatment procedures, e.g. postoperative radiotherapy or earlier androgen depletion, can improve quality of life or even prolong life for the patients concerned (Chapter 9). However, there is no doubt that rising t-PSA values after radical prostatectomy constitute a considerable psychological burden for the patient [34].
Conclusion
It is not possible to say at prent whether the benefit a patient may derive from the available adjuvant treatment procedures justifies the earlier distress which he may suffer as a result of "ultransitive" PSA assays. Before being told PSA concentrations measured by “ultransitive” = “hypernsitive” assays, patients should therefore be thoroughly informed about the wide variation of PSA concentrations in the very low measuring range and about the frequency of fal positive test results. If this has not been duly explained to the patient or if the possibility of unnecessary distress can still not be ruled out, the doctor should refrain from reporting the low PSA concentrations to the patient.
References
1. Alanen KA, Kuopio T, Koskinen PJ, Nevalainen TJ. Immunohistochemical labelling for prostate sp
ecific antigen in non-prostatic tissues. Pathology, Rearch & Practice 1996; 192: 233-7.
2. Arai Y, Onishi H, Oishi K, Takeuchi H, Yoshida O. U of a new hypernsitive assay for the detection of prostate specific antigen in prostate cancer. Jpn J Clin Oncol 1993; 23: 110-5.
3. Björk T, Ljungberg B, Piironen T, Abrahamsson PA, Pettersson K, Cockett AT, Lilja H. Rapid exponential elimination of free prostate-specific antigen contrasts the slow, capacity-limited elimination of PSA complexed to alpha 1-antichymotrypsin from rum. Urology 1998; 51: 57-62.
4. Bock JL, Klee GG. How nsitive is a prostate-specific antigen measurement? How nsitive does it need to be? Arch Pathol Lab Med 2004; 128: 341-3.
5. Breul J, Pickl U, Hartung R. PSA in urine and saliva. Z Urol Poster 3: 40-41, 1993.
6. Breul J, Pickl U, Schaff J. Extraprostatic production of prostate specific antigen is under hormonal control. J Urol 1997; 157: 212-3.
7. Brown EN, McDermott TJ, Bloch KJ, McCollom AD. Defining the smallest analyte concentration an immunoassay can measure. Clin Chem 1996; 42: 893-903.
朗诵培训
8. De Angelis G, Brandt B, Schmid HP, Semjonow A. Vom Antigen zum Tumormarker, Forschungrgebnis zu PSA und ihre klinische Umtzung. Urologe A 2000; 39: 309-12.
9. Diamandis EP, Yu H. Prostate-specific antigen and lack of specificity for prostate cells. Lancet 1994 Nov 12,344(8933):1371-2. Lancet 1995; 345: 1186.
10. Diamandis EP, Yu H. Nonprostatic sources of prostate-specific antigen. Urol Clin North Am 1997; 24: 275-82.
11. Doherty AP, Bower M, Smith GL, Miano R, Mannion EM, Mitchell H, Christmas TJ. Undetectable ultransitive PSA after radical prostatectomy for prostate cancer predicts relap-free survival. Br J Cancer 2000; 83: 1432-6.
12. Elgamal AA, Ectors NL, Sunardhi Widyaputra S, van Poppel HP, van Damme BJ, Baert LV. Detection of prostate specific antigen in pancreas and salivary glands: a potential impact on prostate cancer overestimation. J Urol 1996; 156: 464-8.
13. Ellis WJ, Veslla RL, Noteboom JL, Lange PH, Wolfert RL, Rittenhou HG. Early detection of recurrent prostate cancer with an ultransitive chemiluminescent prostate-specific antigen assay. Urology 1997; 50: 573-9.
14. Filella X, Molina R, Alcover J, Menendez V, Gimenez N, Jo J, Carretero P, Ballesta AM. Prostate-specific antigen detection by ultransitive assay in samples from women. Prostate 1996; 29: 311-6.
15. Fornara P, Semjonow A, Hrsg. PSA: Der Weg zum Befund - Präanalytik und Analytik des prostataspezifischen Antigens. München: Zuckschwerdt Verlag, 2002.
16. Golz R, Schubert GE. Prostatic specific antigen: immunoreactivity in urachal remnants. J Urol 1989; 141: 1480-2.
17. Graves HC. Nonprostatic sources of prostate-specific antigen: a steroid hormone-dependent phenomenon? Clin Chem 1995; 41: 7-9.
18. Hae A, Huland E, Graefen M, Hammerer P, Noldus J, Huland H. Ultransitive detection of prostate specific antigen in the followup of 422 patients after radical prostatectomy. J Urol 1999; 161: 1206-11.
19. Hae A, Huland E, Graefen M, Huland H. Supernsitive PSA-analysis after radical prostatectomy: a powerful tool to reduce the time gap between surgery and evidence of biochemical failure. Anticancer Res 1999; 19: 2641-4.
20. Hagendorff G, Schuff WP, Stibbe W, Mast WP, Scheit K. The determination of prostate-specific antigen (PSA) in human female ra by means of a nsitive ELISA. J Lab Med 1996; 20: 301-2.
21. Harma H, Soukka T, Lonnberg S, Paukkunen J, Tarkkinen P, Lövgren T. Zeptomole detection nsitivity of prostate-specific antigen in a rapid microtitre plate assay using time-resolved fluorescence. Luminescence 2000; 15: 351-5.
22. Hautmann S, Huland E, Grupp C, Hae A, Huland H. Super-nsitive prostate-specific antigen (PSA) in rum of women with benign breast dia or breast cancer. Anticancer Res 2000; 20: 2151-4.
23. Hudson MA, Bahnson RR, Catalona WJ. Clinical u of prostate specific antigen in patients with prostate cancer. J Urol 1989; 142: 1011-7.
24. Junker R, Brandt B, Semjonow A, Assmann G. Measurement of prostate-specific antigen: no advantage to ultransitive assays? J Natl Cancer Inst 1996; 88: 1594-5.
25. Lightner DJ, Lange PH, Reddy PK, Moore L. Prostate specific antigen and local recurrence after radical prostatectomy. J Urol 1990; 144: 921-6.
26. Müller U, Hagendorff G, Stibbe W, Schuff-Werner P. Prostate specific antigen (PSA) in rum samples of female patients: possible pitfalls in evaluating the analytical nsitivity of ultransitive PSA-assays. Anticancer Res 1997; 17: 3067-9.
27. Oberpenning F, Schmid HP, Fuchs-Surdel W, Hertle L, Semjonow A. The impact of intraoperative manipulation of the prostate on total and free prostate-specific antigen. Int J Biol Markers 2002; 17: 154-60.
28. Oesterling JE, Tekchandani AH, Martin SK, Bergstralh EJ, Reichstein E, Diamandis EP, Yemoto C, Stamey TA. The periurethral glands do not significantly influence the rum prostate specific antigen concentration. J Urol 1996; 155: 1658-60.
29. Parish DC. Prostate-specific antigen in the breast. Endocr Relat Cancer 1998; 5: 223-9.
30. Prestigiacomo AF, Stamey TA. A comparison of 4 ultransitive prostate specific antigen assays for early detection of residual cancer after radical prostatectomy. J Urol 1994; 152: 1515-9.
31. Price CP, Allard J, Davies G, Dawnay A, Duffy MJ, France M, Mandarino G, Ward AM, Patel B, Sibley P, Sturgeon C. Pre- and post-analytical factors that may influence u of rum prostate specicustom什么意思
fic antigen and its isoforms in a screening programme for prostate cancer. Ann Clin Biochem 2001; 38: 188-216.
bottled32. Pruthi RS, Hae A, Huland E, Stamey TA. U of rum concentration techniques to enhance early detection of recurrent prostate cancer after radical prostatectomy. Urology 1997; 49: 404-10.
33. Rittenhou HG, Finlay JA, Mikolajczyk SD, Partin AW. Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two cloly related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998; 35: 275-368.
34. Semjonow A, Albrecht W, Bialk P, Gerl A, Lamerz R, Schmid HP, van Poppel H. Tumour markers in prostate cancer: EGTM recommendations. European Group on Tumour Markers.Anticancer Res 1999; 19: 2799-801.
35. Semjonow A, Brandt B, Oberpenning F, Hertle L. Unterschiedliche Bestimmungsverfahren erschweren die Interpretation des prostataspezifischen Antigens. Urologe A 1995; 34: 303-15.
36. Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L. Discordance of assay methods creates pitfalls for the interpretation of prostate-specific antigen values. Prostate 1996; 7: 3-16.
37. Semjonow A, Hamm M, Rathert P. Half-life of prostate-specific antigen after radical prostatectomy: The decisive predictor of curative treatment? Eur Urol 1992; 21: 200-5.南师大自考
38. Semjonow A, Schmid HP. The ri and fall of PSA: clinical implications of prostate specific antigen kinetics. Urol Res 2002; 30: 85-8.
39. Sölétormos G, Semjonow A, Sibley PEC, Lamerz R, Hyltoft Petern P, Albrecht W, Bialk P, Gion M, Junker F, Schmid HP, van
Poppel H, on behalf of The European Group on Tumour Markers (EGTM). Biological Variation of Total Prostate-Specific Antigen: A European Group on Tumor Markers (EGTM) Survey of Published Estimates and Conquences for Clinical Practice. Clin Chem 2005; 51 (8): 1342-51, 2005.
40. Soukka T, Antonen K, Harma H, Pelkkikangas AM, Huhtinen P, Lövgren T. Highly nsitive immunoassay of free prostate-specific antigen in rum using europium(III) nanoparticle label technology. Clin Chim Acta 2003; 328: 45-58.
41. Stamey TA. Lower limits of detection, biological detection limits, functional nsitivity, or residual cancer detection limit? Sensitivity reports on prostate-specific antigen assays mislead clinicians. Clin Chem 1996; 42: 849-52.
42. Takayama TK, Veslla RL, Brawer MK, Noteboom J, Lange PH. The enhanced detection of persistent dia after prostatectomy with a new prostate specific antigen immunoassay. J Urol 1993; 150: 374-8.
43. Takayama TK, Veslla RL, Lange PH. A brief review of ultransitive prostate-specific antigen assays for the evaluation of patients after radical prostatectomy.World J Urol 1993; 11: 192-5.
44. van Ierl MP, Thomas CM, Segers MF, Witjes WP, Debruyne FM, Oosterhof GO. The u of ‘ultransitive’ prostate-specific antigen assays in the detection of biochemical recurrence after radical prostatectomy. Br J Urol 1996; 77: 418-22.
45. Ward AM, Catto JW, Hamdy FC. Prostate specific antigen: biology, biochemistry and available commercial assays. Ann Clin Biochem 2001; 38: 633-51.
46. Witherspoon LR. Early detection of cancer relap after prostatectomy using very nsitive prostate-specific antigen measurements. Br J Urol 1997; 79: 82-6.
47. Witherspoon LR, Lapeyrolerie T. Sensitive prostate specific antigen measurements identify men with long dia-free intervals and differentiate aggressive from indolent cancer recurrences within 2 years after radical prostatectomy. J Urol 1997; 157: 1322-8.
48. Yu H, Diamandis EP. Measurement of rum prostate specific antigen levels in women and in prostatectomized men with an ultransitive immunoassay technique. J Urol 1995; 153: 1004-8.
49. Zarghami N, Grass L, Sauter ER, Diamandis EP. Prostate-specific antigen in rum during the menstrual cycle. Clin Chem 1997; 43: 1862-7.
