Skip to main content
Postgraduate Medical Journal logoLink to Postgraduate Medical Journal
. 2002 Nov;78(925):646–650. doi: 10.1136/pmj.78.925.646

Improving the utility of prostate specific antigen (PSA) in the diagnosis of prostate cancer: the use of PSA derivatives and novel markers

S Jain 1, A Bhojwani 1, J Mellon 1
PMCID: PMC1742550  PMID: 12496317

Abstract

Prostate specific antigen (PSA) testing is now a routine part of the investigation of men with suspected prostate cancer. While a very useful test it still has its problems, in particular its lack of specificity means abnormal results are often caused by benign disease. This review describes the current problems with PSA testing in prostate cancer diagnosis and highlights potential ways in which these may be reduced.

Full Text

The Full Text of this article is available as a PDF (133.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allard W. J., Zhou Z., Yeung K. K. Novel immunoassay for the measurement of complexed prostate-specific antigen in serum. Clin Chem. 1998 Jun;44(6 Pt 1):1216–1223. [PubMed] [Google Scholar]
  2. Becker C., Piironen T., Kiviniemi J., Lilja H., Pettersson K. Sensitive and specific immunodetection of human glandular kallikrein 2 in serum. Clin Chem. 2000 Feb;46(2):198–206. [PubMed] [Google Scholar]
  3. Becker C., Piironen T., Pettersson K., Hugosson J., Lilja H. Clinical value of human glandular kallikrein 2 and free and total prostate-specific antigen in serum from a population of men with prostate-specific antigen levels 3.0 ng/mL or greater. Urology. 2000 May;55(5):694–699. doi: 10.1016/s0090-4295(99)00585-3. [DOI] [PubMed] [Google Scholar]
  4. Beckett M. L., Cazares L. H., Vlahou A., Schellhammer P. F., Wright G. L., Jr Prostate-specific membrane antigen levels in sera from healthy men and patients with benign prostate hyperplasia or prostate cancer. Clin Cancer Res. 1999 Dec;5(12):4034–4040. [PubMed] [Google Scholar]
  5. Benson M. C., Whang I. S., Olsson C. A., McMahon D. J., Cooner W. H. The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen. J Urol. 1992 Mar;147(3 Pt 2):817–821. doi: 10.1016/s0022-5347(17)37394-9. [DOI] [PubMed] [Google Scholar]
  6. Björk T., Bjartell A., Abrahamsson P. A., Hulkko S., di Sant'Agnese A., Lilja H. Alpha 1-antichymotrypsin production in PSA-producing cells is common in prostate cancer but rare in benign prostatic hyperplasia. Urology. 1994 Apr;43(4):427–434. doi: 10.1016/0090-4295(94)90225-9. [DOI] [PubMed] [Google Scholar]
  7. Borer J. G., Sherman J., Solomon M. C., Plawker M. W., Macchia R. J. Age specific prostate specific antigen reference ranges: population specific. J Urol. 1998 Feb;159(2):444–448. doi: 10.1016/s0022-5347(01)63945-4. [DOI] [PubMed] [Google Scholar]
  8. Brawer M. K., Aramburu E. A., Chen G. L., Preston S. D., Ellis W. J. The inability of prostate specific antigen index to enhance the predictive the value of prostate specific antigen in the diagnosis of prostatic carcinoma. J Urol. 1993 Aug;150(2 Pt 1):369–373. doi: 10.1016/s0022-5347(17)35485-x. [DOI] [PubMed] [Google Scholar]
  9. Brawer M. K., Cheli C. D., Neaman I. E., Goldblatt J., Smith C., Schwartz M. K., Bruzek D. J., Morris D. L., Sokoll L. J., Chan D. W. Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. J Urol. 2000 May;163(5):1476–1480. [PubMed] [Google Scholar]
  10. Brawer M. K., Chetner M. P., Beatie J., Buchner D. M., Vessella R. L., Lange P. H. Screening for prostatic carcinoma with prostate specific antigen. J Urol. 1992 Mar;147(3 Pt 2):841–845. doi: 10.1016/s0022-5347(17)37401-3. [DOI] [PubMed] [Google Scholar]
  11. Carter H. B., Pearson J. D., Metter E. J., Brant L. J., Chan D. W., Andres R., Fozard J. L., Walsh P. C. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992 Apr 22;267(16):2215–2220. [PMC free article] [PubMed] [Google Scholar]
  12. Catalona W. J., Beiser J. A., Smith D. S. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol. 1997 Dec;158(6):2162–2167. doi: 10.1016/s0022-5347(01)68187-4. [DOI] [PubMed] [Google Scholar]
  13. Catalona W. J., Hudson M. A., Scardino P. T., Richie J. P., Ahmann F. R., Flanigan R. C., deKernion J. B., Ratliff T. L., Kavoussi L. R., Dalkin B. L. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol. 1994 Dec;152(6 Pt 1):2037–2042. doi: 10.1016/s0022-5347(17)32300-5. [DOI] [PubMed] [Google Scholar]
  14. Catalona W. J., Partin A. W., Slawin K. M., Brawer M. K., Flanigan R. C., Patel A., Richie J. P., deKernion J. B., Walsh P. C., Scardino P. T. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998 May 20;279(19):1542–1547. doi: 10.1001/jama.279.19.1542. [DOI] [PubMed] [Google Scholar]
  15. Catalona W. J., Smith D. S., Ornstein D. K. 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 May 14;277(18):1452–1455. [PubMed] [Google Scholar]
  16. Catalona W. J., Smith D. S., Ratliff T. L., Dodds K. M., Coplen D. E., Yuan J. J., Petros J. A., Andriole G. L. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991 Apr 25;324(17):1156–1161. doi: 10.1056/NEJM199104253241702. [DOI] [PubMed] [Google Scholar]
  17. Darson M. F., Pacelli A., Roche P., Rittenhouse H. G., Wolfert R. L., Young C. Y., Klee G. G., Tindall D. J., Bostwick D. G. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology. 1997 Jun;49(6):857–862. doi: 10.1016/s0090-4295(97)00108-8. [DOI] [PubMed] [Google Scholar]
  18. Diamandis E. P., Yousef G. M., Luo L. Y., Magklara A., Obiezu C. V. The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab. 2000 Mar;11(2):54–60. doi: 10.1016/s1043-2760(99)00225-8. [DOI] [PubMed] [Google Scholar]
  19. Djavan B., Zlotta A. R., Byttebier G., Shariat S., Omar M., Schulman C. C., Marberger M. Prostate specific antigen density of the transition zone for early detection of prostate cancer. J Urol. 1998 Aug;160(2):411–419. [PubMed] [Google Scholar]
  20. Djavan B., Zlotta A., Remzi M., Ghawidel K., Basharkhah A., Schulman C. C., Marberger M. Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol. 2000 Apr;163(4):1144–1149. [PubMed] [Google Scholar]
  21. Finlay J. A., Evans C. L., Day J. R., Payne J. K., Mikolajczyk S. D., Millar L. S., Kuus-Reichel K., Wolfert R. L., Rittenhouse H. G. Development of monoclonal antibodies specific for human glandular kallikrein (hK2): development of a dual antibody immunoassay for hK2 with negligible prostate-specific antigen cross-reactivity. Urology. 1998 May;51(5):804–809. doi: 10.1016/s0090-4295(98)00107-1. [DOI] [PubMed] [Google Scholar]
  22. Finne P., Zhang W. M., Auvinen A., Leinonen J., Mättänen L., Rannikko S., Tammela T. L., Stenman U. H. Use of the complex between prostate specific antigen and alpha 1-protease inhibitor for screening prostate cancer. J Urol. 2000 Dec;164(6):1956–1960. [PubMed] [Google Scholar]
  23. Horoszewicz J. S., Kawinski E., Murphy G. P. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res. 1987 Sep-Oct;7(5B):927–935. [PubMed] [Google Scholar]
  24. Israeli R. S., Powell C. T., Fair W. R., Heston W. D. Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res. 1993 Jan 15;53(2):227–230. [PubMed] [Google Scholar]
  25. Komatsu K., Wehner N., Prestigiacomo A. F., Chen Z., Stamey T. A. Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology. 1996 Mar;47(3):343–346. doi: 10.1016/s0090-4295(99)80450-6. [DOI] [PubMed] [Google Scholar]
  26. Kumar A., Mikolajczyk S. D., Goel A. S., Millar L. S., Saedi M. S. Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2. Cancer Res. 1997 Aug 1;57(15):3111–3114. [PubMed] [Google Scholar]
  27. Leinonen J., Zhang W. M., Stenman U. H. Complex formation between PSA isoenzymes and protease inhibitors. J Urol. 1996 Mar;155(3):1099–1103. [PubMed] [Google Scholar]
  28. Lilja H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest. 1985 Nov;76(5):1899–1903. doi: 10.1172/JCI112185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lilja H., Christensson A., Dahlén U., Matikainen M. T., Nilsson O., Pettersson K., Lövgren T. Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem. 1991 Sep;37(9):1618–1625. [PubMed] [Google Scholar]
  30. Lujan M., Paez A., Llanes L., Miravalles E., Berenguer A. Prostate specific antigen density. Is there a role for this parameter when screening for prostate cancer? Prostate Cancer Prostatic Dis. 2001;4(3):146–149. doi: 10.1038/sj.pcan.4500509. [DOI] [PubMed] [Google Scholar]
  31. Mitchell I. D., Croal B. L., Dickie A., Cohen N. P., Ross I. A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer. J Urol. 2001 May;165(5):1549–1553. [PubMed] [Google Scholar]
  32. Morgan T. O., Jacobsen S. J., McCarthy W. F., Jacobson D. J., McLeod D. G., Moul J. W. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med. 1996 Aug 1;335(5):304–310. doi: 10.1056/NEJM199608013350502. [DOI] [PubMed] [Google Scholar]
  33. Nixon R. G., Meyer G. E., Blase A. B., Gold M. H., Brawer M. K. Comparison of 3 investigational assays for the free form of prostate specific antigen. J Urol. 1998 Aug;160(2):420–425. [PubMed] [Google Scholar]
  34. Nixon R. G., Wener M. H., Smith K. M., Parson R. E., Strobel S. A., Brawer M. K. Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients. J Urol. 1997 Jun;157(6):2183–2190. doi: 10.1016/s0022-5347(01)64711-6. [DOI] [PubMed] [Google Scholar]
  35. Oesterling J. E., Cooner W. H., Jacobsen S. J., Guess H. A., Lieber M. M. Influence of patient age on the serum PSA concentration. An important clinical observation. Urol Clin North Am. 1993 Nov;20(4):671–680. [PubMed] [Google Scholar]
  36. Oesterling J. E., Jacobsen S. J., Chute C. G., Guess H. A., Girman C. J., Panser L. A., Lieber M. M. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. JAMA. 1993 Aug 18;270(7):860–864. [PubMed] [Google Scholar]
  37. Oesterling J. E. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol. 1991 May;145(5):907–923. doi: 10.1016/s0022-5347(17)38491-4. [DOI] [PubMed] [Google Scholar]
  38. Ohori M., Dunn J. K., Scardino P. T. Is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer? Urology. 1995 Nov;46(5):666–671. doi: 10.1016/S0090-4295(99)80298-2. [DOI] [PubMed] [Google Scholar]
  39. Partin A. W., Catalona W. J., Finlay J. A., Darte C., Tindall D. J., Young C. Y., Klee G. G., Chan D. W., Rittenhouse H. G., Wolfert R. L. Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology. 1999 Nov;54(5):839–845. doi: 10.1016/s0090-4295(99)00270-8. [DOI] [PubMed] [Google Scholar]
  40. Partin A. W., Criley S. R., Subong E. N., Zincke H., Walsh P. C., Oesterling J. E. Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: A pathological analysis. J Urol. 1996 Apr;155(4):1336–1339. [PubMed] [Google Scholar]
  41. Patel D., White P. A., Milford Ward A. A comparison of six commercial assays for total and free prostate specific antigen (PSA): the predictive value of the ratio of free to total PSA. BJU Int. 2000 Apr;85(6):686–689. doi: 10.1046/j.1464-410x.2000.00526.x. [DOI] [PubMed] [Google Scholar]
  42. Silver D. A., Pellicer I., Fair W. R., Heston W. D., Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997 Jan;3(1):81–85. [PubMed] [Google Scholar]
  43. Smith D. S., Catalona W. J. Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection. J Urol. 1994 Oct;152(4):1163–1167. doi: 10.1016/s0022-5347(17)32528-4. [DOI] [PubMed] [Google Scholar]
  44. Stamey T. A., Yang N., Hay A. R., McNeal J. E., Freiha F. S., Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987 Oct 8;317(15):909–916. doi: 10.1056/NEJM198710083171501. [DOI] [PubMed] [Google Scholar]
  45. Stamey T. A., Yemoto C. E. Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume. J Urol. 2000 Jan;163(1):119–126. [PubMed] [Google Scholar]
  46. Stenman U. H., Leinonen J., Alfthan H., Rannikko S., Tuhkanen K., Alfthan O. A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res. 1991 Jan 1;51(1):222–226. [PubMed] [Google Scholar]
  47. Su S. L., Boynton A. L., Holmes E. H., Elgamal A. A., Murphy G. P. Detection of extraprostatic prostate cells utilizing reverse transcription-polymerase chain reaction. Semin Surg Oncol. 2000 Jan-Feb;18(1):17–28. doi: 10.1002/(sici)1098-2388(200001/02)18:1<17::aid-ssu4>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  48. Xiao Z., Adam B. L., Cazares L. H., Clements M. A., Davis J. W., Schellhammer P. F., Dalmasso E. A., Wright G. L., Jr Quantitation of serum prostate-specific membrane antigen by a novel protein biochip immunoassay discriminates benign from malignant prostate disease. Cancer Res. 2001 Aug 15;61(16):6029–6033. [PubMed] [Google Scholar]
  49. Zhang W. M., Finne P., Leinonen J., Salo J., Stenman U. H. Determination of prostate-specific antigen complexed to alpha(2)-macroglobulin in serum increases the specificity of free to total PSA for prostate cancer. Urology. 2000 Aug 1;56(2):267–272. doi: 10.1016/s0090-4295(00)00609-9. [DOI] [PubMed] [Google Scholar]
  50. Zhang W. M., Finne P., Leinonen J., Vesalainen S., Nordling S., Stenman U. H. Measurement of the complex between prostate-specific antigen and alpha1-protease inhibitor in serum. Clin Chem. 1999 Jun;45(6 Pt 1):814–821. [PubMed] [Google Scholar]

Articles from Postgraduate Medical Journal are provided here courtesy of BMJ Publishing Group

RESOURCES