Percent Free Prostate-Specific Antigen: Entering a New Era in the Detection of Prostate Cancer
1997; Elsevier BV; Volume: 72; Issue: 4 Linguagem: Inglês
10.4065/72.4.337
ISSN1942-5546
AutoresApoorva Vashi, Joseph E. Oesterling,
Tópico(s)Hepatitis B Virus Studies
ResumoThe introduction of prostate-specific antigen (PSA) testing into clinical medicine in 1986 revolutionized the management of patients with prostate cancer. The major limitation of this tumor marker stems from its inability to provide a clear distinction between benign prostate disease and prostate cancer, especially in patients with upper limit of normal or slightly increased PSA values. Recent research has established that PSA exists in the serum in several molecular forms. Patients with benign prostatic hyperplasia have more of the free form, whereas those with prostate cancer have more of a complexed form (PSA covalently bound to a,-antichymotrypsin). Several investigations have now confirmed that determining percent free PSA (proportion of free PSA to total PSA) enhances the ability of PSA testing to distinguish between prostate cancer and benign prostatic hyperplasia. In addition, percent free PSA seems to have the greatest clinical significance in patients whose total PSA values range from 2.5 or 3.0 ng/mL (lower limit) to 10.0 ng/mL (upper limit). When the total PSA value is in the normal range (2.5 or 3.0 to 4.0 ng/mL), percent free PSA makes PSA a more sensitive test (increases cancer detection). When the total PSA level is minimally increased (4.1 to 10.0 ng/mL), percent free PSA makes PSA a more specific test (eliminates performance of unnecessary prostate biopsies). Although further work remains, it seems that percent free PSA can substantially improve the clinical utility of the PSA test for detecting early, curable prostate cancer. The introduction of prostate-specific antigen (PSA) testing into clinical medicine in 1986 revolutionized the management of patients with prostate cancer. The major limitation of this tumor marker stems from its inability to provide a clear distinction between benign prostate disease and prostate cancer, especially in patients with upper limit of normal or slightly increased PSA values. Recent research has established that PSA exists in the serum in several molecular forms. Patients with benign prostatic hyperplasia have more of the free form, whereas those with prostate cancer have more of a complexed form (PSA covalently bound to a,-antichymotrypsin). Several investigations have now confirmed that determining percent free PSA (proportion of free PSA to total PSA) enhances the ability of PSA testing to distinguish between prostate cancer and benign prostatic hyperplasia. In addition, percent free PSA seems to have the greatest clinical significance in patients whose total PSA values range from 2.5 or 3.0 ng/mL (lower limit) to 10.0 ng/mL (upper limit). When the total PSA value is in the normal range (2.5 or 3.0 to 4.0 ng/mL), percent free PSA makes PSA a more sensitive test (increases cancer detection). When the total PSA level is minimally increased (4.1 to 10.0 ng/mL), percent free PSA makes PSA a more specific test (eliminates performance of unnecessary prostate biopsies). Although further work remains, it seems that percent free PSA can substantially improve the clinical utility of the PSA test for detecting early, curable prostate cancer. On the basis of the more than 334,000 new cases and 41,800 deaths that are predicted for 1997, prostate cancer is the most commonly detected cancer in men and the second leading cause of death due to cancer.1Parker SL Tong T Bolden S Wingo PA Cancer statistics, 1997.CA Cancer J Clin. 1997; 47: 5-27Crossref PubMed Scopus (2343) Google Scholar In order to decrease the mortality rate associated with this disease, efforts must be focused on early detection of organ-confined cancer in young men; no curative therapy is available for systemic prostate cancer. Since its discovery in 1979,2Wang MC Valenzuela LA Murphy GP Chu TM Purification of a human prostate specific antigen.Invest Urol. 1979; 17: 159-163PubMed Google Scholar prostate-specific antigen (PSA) has become the most clinically useful tumor marker available for the diagnosis and management of prostate cancer.3Oesterling JE Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate.J Urol. 1991; 145: 907-923Abstract Full Text PDF PubMed Scopus (1173) Google Scholar Studies have demonstrated that PSA testing detects significantly more cancers than does digital rectal examination,4Brawer MK Chetner MP Beatie J Büchner DM Vessella RL Lange PH Screening for prostatic carcinoma with prostate specific antigen.JUrol. 1992; 147: 841-845Google Scholar, 5Catalona WJ Richie JP Ahmann FR Hudson MA Scardino PT Flanigan RC et al.Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men.J Urol. 1994; 151: 1283-1290Abstract Full Text PDF PubMed Scopus (1331) Google Scholar as well as a greater proportion of organ-confined cancers.6Catalona WJ Smith DS Ratliff TL Basler JW Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening.JAMA. 1993; 270: 948-954Crossref PubMed Scopus (863) Google Scholar Originally, investigators believed that PSA testing might detect clinically insignificant cancers, but current evidence clearly shows that most PSA-detected prostate cancers have the pathologic features of clinically important, life-threatening tumors.7Smith DS Catalona WJ The nature of prostate cancer detected through prostate specific antigen based screening.J Urol. 1994; 152: 1732-1736Abstract Full Text PDF PubMed Google Scholar, 8Epstein JI Walsh PC Carmichael M Brendler CB Pathologic and clinical findings to predict tumor extent of nonpalpable (stage Tic) prostate cancer.JAMA. 1994; 271: 368-374Crossref PubMed Scopus (1590) Google Scholar, 9Stormont TJ Farrow GM Myers RP Blute ML Zincke H Wilson TM et al.Clinical stage BO or Tic prostate cancer: nonpalpable disease identified by elevated serum prostate-specific antigen concentration.Urology. 1993; 41: 3-8Abstract Full Text PDF PubMed Scopus (79) Google Scholar Although PSA is a powerful clinical tool to monitor disease progression and manage patients with prostate cancer,3Oesterling JE Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate.J Urol. 1991; 145: 907-923Abstract Full Text PDF PubMed Scopus (1173) Google Scholar in its current form, PSA lacks sufficient sensitivity and specificity to be considered the ideal tumor marker for the early detection of prostate cancer. The use of the traditional cutpoint of 4.0 ng/mL to distinguish between “normal” and “abnormal” PSA values has several limitatins. Because PSA is organ specific and not cancer specific, considerable overlap in PSA values exists between patients with prostate cancer and those with benign conditions such as benign prostatic hyperplasia and prostatitis.10Stamey TA Yang N Hay AR McNeal JE Freiha FS Redwine E Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate.NEnglJMed. 1987; 317: 909-916Crossref PubMed Scopus (2014) Google Scholar, 11Monda JM Barry MJ Oesterling JE Prostate specific antigen cannot distinguish stage Tía (Al) prostate cancer from benign prostatic hyperplasia.JUrol. 1994; 151: 1291-1295Google Scholar In addition, 38 to 48% of patients with clinically significant organ-confined cancer have a normal PSA value of 4.0 ng/mL or less.12Hudson MA Bahnson RR Catalona WJ Clinical use of prostate specific antigen in patients with prostate cancer.J Urol. 1989; 142: 1011-1017Abstract Full Text PDF PubMed Scopus (414) Google Scholar, 13Lange PH Ercole CJ Lightner DJ Fraley EE Vessella R The value of serum prostate specific antigen determinations before and after radical prostatectomy.JUrol. 1989; 141: 873-879Google Scholar In order to address these concerns, the concepts of PSA density (PSAD),14Benson MC Whang IS Olsson CA McMahon DJ Cooner WH The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen.J Urol. 1992; 147: 817-821Abstract Full Text PDF PubMed Google Scholar, 15Seaman E Whang M Olsson CA Katz A Cooner WH Benson MC PSA density (PSAD): role in patient evaluation and management.Urol Clin North Am. 1993 Nov; 20: 653-663PubMed Google Scholar PSA velocity (PSAV),16Oesterling JE Chute CG Jacobsen SJ Guess HA Panser LA Johnson CL et al.Longitudinal changes in serum PSA (PSA velocity) in a community-based cohort of men [abstract].JUrol. 1993; 149: 412AGoogle Scholar, 17Carter HB Pearson JD Metter EJ Brant LJ Chan DW Andres R et al.Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease.JAMA. 1992; 267: 2215-2220Crossref PubMed Scopus (933) Google Scholar and age-specific reference ranges18Oesterling JE Jacobsen SJ Chute CG Guess HA Girman CJ Panser LA et al.Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.JAMA. 1993; 270: 860-864Crossref PubMed Scopus (1192) Google Scholar, 19Dalkin BL Ahmann F Southwick P Bottaccini MR Derivation of normal prostate specific antigen (PSA) level by age [abstract].J Urol. 1993; 149: 413AGoogle Scholar, 20Collins GN Lee RJ McKelvie GB Rogers AC Hehir M Relationship between prostate specific antigen, prostate volume and age in the benign prostate.BrJUrol. 1993; 71: 445-450Google Scholar have been introduced and investigated. In addition, recent studies have demonstrated that PSA is present in the serum in several molecular forms.21Christensson A Laurell CB Lilja H Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors.Eur J Biochem. 1990; 194: 755-763Crossref PubMed Scopus (599) Google Scholar, 22Lilja H Christensson A Dahlén U Matikainen M-T Nilsson O Pettersson K et al.Prostate-specific antigen in serum occurs predominantly in complex with a,-antichymotrypsin.ClinChem. 1991; 37: 1618-1625Google Scholar, 23Stenman U-H Leinonen J Alfthan H Rannikko S Tuhkanen K Alfthan O A complex between prostate-specific antigen and a,-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; 51: 222-226PubMed Google Scholar, 24Christensson A Björk T Nilsson O Dahlén U Matikainen M Cockett ATK et al.Serum prostate specific antigen complexed to al-antichymotrypsin as an indicator of prostate cancer.JUrol. 1993; 150: 100-105Google Scholar Preliminary investigations have illustrated the potential benefits of using these molecular forms of PSA to enhance the clinical utility of PSA testing in the early detection of prostate cancer. These studies suggest that the ability to measure these specific forms of PSA in the serum can enhance the capability of PSA to distinguish between patients with prostate cancer and those with benign disease.23Stenman U-H Leinonen J Alfthan H Rannikko S Tuhkanen K Alfthan O A complex between prostate-specific antigen and a,-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; 51: 222-226PubMed Google Scholar, 24Christensson A Björk T Nilsson O Dahlén U Matikainen M Cockett ATK et al.Serum prostate specific antigen complexed to al-antichymotrypsin as an indicator of prostate cancer.JUrol. 1993; 150: 100-105Google Scholar, 25Catalona WJ Smith DS Wolfert RL Wang TJ Rittenhouse HG Ratliff TL et al.Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening.JAMA. 1995; 274: 1214-1220Crossref PubMed Google Scholar, 26Luderer AA Chen YT Soriano TF Kramp WJ Carlson G Cuny C et al.Measurement of the proportion of free to total prostate-specific antigen improves diagnostic performance of prostate-specific antigen in the diagnostic gray zone of total prostate-specific antigen.Urology. 1995; 46: 187-194Abstract Full Text PDF PubMed Scopus (276) Google Scholar This represents a major step forward for men with a serum PSA value in the upper limit of normal or a mildly increased level. The goals of improving the PSA test are twofold: to enhance sensitivity (increase cancer detection) and to improve specificity (eliminate costly and invasive prostate biopsies that show normal results). PS AD, PSAV, and age-specific reference ranges have been proposed to achieve these goals. In 1992, Benson and associates14Benson MC Whang IS Olsson CA McMahon DJ Cooner WH The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen.J Urol. 1992; 147: 817-821Abstract Full Text PDF PubMed Google Scholar introduced the concept of PSAD to distinguish PSA increases due to prostate cancer from those due to benign disease. PSAD is the ratio of the serum PSA concentration and prostate volume, as determined by transrectal ultrasonography. These investigators concluded that a PSAD of 0.15 or less was normal. Unfortunately, PSAD is limited by several factors, including the cost and invasiveness of the transrectal prostate ultrasound study and the inaccuracy of ultrasound to determine the precise prostate volume.’8Epstein JI Walsh PC Carmichael M Brendler CB Pathologic and clinical findings to predict tumor extent of nonpalpable (stage Tic) prostate cancer.JAMA. 1994; 271: 368-374Crossref PubMed Scopus (1590) Google Scholar, 27Mettlin C Littrup PJ Kane RA Murphy GP Lee F Chesley A et al.Relative sensitivity and specificity of serum prostate specific antigen (PSA) level compared with age-referenced PSA, PSA density, and PSA change: data from the American Cancer Society National Prostate Cancer Detection Project.Cancer. 1994; 74: 1615-1620Crossref PubMed Scopus (135) Google Scholar In addition, a large screening study by Catalona and colleagues28Catalona WJ Richie JP deKernion JB Ahmann FR Ratliff TL Dalkin BL et al.Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves.J Urol. 1994; 152: 2031-2036Abstract Full Text PDF PubMed Scopus (237) Google Scholar showed no benefit of PSAD over a single PSA cutpoint of 4.0 ng/mL. Carter and coworkers17Carter HB Pearson JD Metter EJ Brant LJ Chan DW Andres R et al.Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease.JAMA. 1992; 267: 2215-2220Crossref PubMed Scopus (933) Google Scholar introduced the concept of PSAV to enhance the clinical utility of the PSA test. They concluded that a PSAV of 0.75 ng/mL or greater per year was a concern for the presence of prostate cancer. In general, the concept is useful; however, it is limited by the intrinsic variability of PSA testing and the fact that the same assay and laboratory should be used for each measurement.27Mettlin C Littrup PJ Kane RA Murphy GP Lee F Chesley A et al.Relative sensitivity and specificity of serum prostate specific antigen (PSA) level compared with age-referenced PSA, PSA density, and PSA change: data from the American Cancer Society National Prostate Cancer Detection Project.Cancer. 1994; 74: 1615-1620Crossref PubMed Scopus (135) Google Scholar, 28Catalona WJ Richie JP deKernion JB Ahmann FR Ratliff TL Dalkin BL et al.Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves.J Urol. 1994; 152: 2031-2036Abstract Full Text PDF PubMed Scopus (237) Google Scholar, 29Smith DS Catalona WJ Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection.JUrol. 1994; 152: 1163-1167Google Scholar In addition, each serum sample should be obtained under similar conditions to control for variations due to infection, ejaculation, and other prostate manipulations.30Tchetgen MB Song JT Strawderman M Jacobsen SJ Oesterling JE Ejaculation increases the serum prostate-specific antigen concentration.Urology. 1996; 47: 511-516Abstract Full Text PDF PubMed Scopus (99) Google Scholar Thus, PSAD and PSAV have practical limitations that minimize their effectiveness. Age-specific reference ranges, as proposed by Oesterling and associates,18Oesterling JE Jacobsen SJ Chute CG Guess HA Girman CJ Panser LA et al.Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.JAMA. 1993; 270: 860-864Crossref PubMed Scopus (1192) Google Scholar represent an effective method of enhancing the clinical utility of the PSA test. These ranges increase the sensitivity of the PSA test in younger men by decreasing the number of false-negative results and improve the specificity in older men by decreasing the number of false-positive results.18Oesterling JE Jacobsen SJ Chute CG Guess HA Girman CJ Panser LA et al.Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.JAMA. 1993; 270: 860-864Crossref PubMed Scopus (1192) Google Scholar The recommended age-specific reference ranges (as proposed by Oesterling and colleagues18Oesterling JE Jacobsen SJ Chute CG Guess HA Girman CJ Panser LA et al.Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.JAMA. 1993; 270: 860-864Crossref PubMed Scopus (1192) Google Scholar) are as follows: 0.0 to 2.5 ng/mL for men 40 to 49 years old, 0.0 to 3.5 ng/mL for men 50 to 59 years old, 0.0 to 4.5 ng/mL for men 60 to 69 years old, and 0.0 to 6.5 ng/mL for men 70 to 79 years old. The concept that the serum PSA concentration correlates directly with the patient's age has been confirmed subsequently in several investigations.19Dalkin BL Ahmann F Southwick P Bottaccini MR Derivation of normal prostate specific antigen (PSA) level by age [abstract].J Urol. 1993; 149: 413AGoogle Scholar, 20Collins GN Lee RJ McKelvie GB Rogers AC Hehir M Relationship between prostate specific antigen, prostate volume and age in the benign prostate.BrJUrol. 1993; 71: 445-450Google Scholar, 31Richardson TD, Oesterling JE. Age-specific reference ranges for serum PSA. Urol Clin North Am [in press]Google Scholar A limitation of the work by Oesterling and coworkers18Oesterling JE Jacobsen SJ Chute CG Guess HA Girman CJ Panser LA et al.Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.JAMA. 1993; 270: 860-864Crossref PubMed Scopus (1192) Google Scholar is that the data were generated from a homogeneous group of white men. Prostate cancer has a lower incidence in Asian men and a higher, more aggressive incidence in black men.32Oesterling JE Kumamoto Y Tsukamoto T Girman CJ Guess HA Masumori N et al.Serum prostate-specific antigen in a community-based population of healthy Japanese men: lower values than for similarly aged white men.BrJUrol. 1995; 75: 347-353Google Scholar, 33Morgan TO Jacobsen SJ McCarthy WF Jacobson DJ McLeod DG Moul JW Age-specific reference ranges for serum prostate-specific antigen in black men.NEnglJMed. 1996; 335: 304-310Crossref PubMed Scopus (368) Google Scholar Oesterling and associates32Oesterling JE Kumamoto Y Tsukamoto T Girman CJ Guess HA Masumori N et al.Serum prostate-specific antigen in a community-based population of healthy Japanese men: lower values than for similarly aged white men.BrJUrol. 1995; 75: 347-353Google Scholar noted a similar increase in serum PSA with advancing age in a cohort of healthy Japanese men; however, the age-specific reference ranges were lower: 0.0 to 2.0 ng/mL for men 40 to 49 years old, 0.0 to 3.0 ng/mL for men 50 to 59 years old, 0.0 to 4.0 ng/mL for men 60 to 69 years old, and 0.0 to 5.0 ng/mL for men 70 to 79 years old.32Oesterling JE Kumamoto Y Tsukamoto T Girman CJ Guess HA Masumori N et al.Serum prostate-specific antigen in a community-based population of healthy Japanese men: lower values than for similarly aged white men.BrJUrol. 1995; 75: 347-353Google Scholar A recent investigation by Morgan and colleagues33Morgan TO Jacobsen SJ McCarthy WF Jacobson DJ McLeod DG Moul JW Age-specific reference ranges for serum prostate-specific antigen in black men.NEnglJMed. 1996; 335: 304-310Crossref PubMed Scopus (368) Google Scholar examined the utility of age-specific reference ranges in a large group of black men. With use of the traditional age-specific reference ranges determined for white men, 41% of cancers would have been overlooked in black men. Therefore, although serum PSA correlated directly with patient age, a separate set of age-specific ranges were determined for black men: 0.0 to 2.0 ng/mL for men 40 to 49 years old, 0.0 to 4.0 ng/mL for men 50 to 59 years old, 0.0 to 4.5 ng/mL for men 60 to 69 years old, and 0.0 to 5.5 ng/mL for men 70 to 79 years old. The recommended age-specific reference ranges for white, Asian, and black men are succinctly summarized in Table 1.Table 1Age-Specific Reference Ranges Based on RaceSerum prostate-specific antigen*Upper limit of normal. (ng/mL)Age (yr)BlackAsianWhite40–492.02.02.550–594.03.03.560–694.54.04.570–795.55.06.5* Upper limit of normal. Open table in a new tab Although many investigations have confirmed the finding that the serum PSA level increases with advancing age, the use of different study populations has produced slightly different cutpoints for the age-specific reference ranges. In addition, the value of wider reference ranges in older men (those older than 60 years) has been questioned by the strong proponents of prostate cancer screening. In a study of 6,630 men, Catalona and coworkers34Catalona WJ Hudson MA Scardino PT Richie JP Ahmann FR Flanigan RC et al.Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves.JUrol. 1994; 152: 2037-2042Google Scholar concluded that a cutpoint of 4.0 ng/mL was superior to age-specific ranges in men older than 60 years because of a potential decrease in cancer detection when age-specific ranges are used for such men. Partin and associates35Partin AW Criley SR Subong EN Zincke H Walsh PC Oesterling JE Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: a pathological analysis.JUrol. 1996; 155: 1336-1339Google Scholar evaluated the pathologic characteristics of prostate tumors detected or overlooked when age-specific reference ranges were used. This investigation supported the use of age-specific reference ranges in men younger than 60 years of age. Failure to detect some organconfined tumors in older men (the clinical significance of these small tumors in older men is unknown), however, led these investigators to conclude that age-specific ranges in men older than 60 years should be studied further. Thus, the search for ways to improve the utility of the PSA test in the early detection of prostate cancer continues. The discovery that PSA exists in the serum in several molecular forms represents an exciting, new approach for improving the clinical utility of the PSA test. The major forms include a noncomplexed or free form and complexes of PSA with the serine protease inhibitors (Xj-antichymotrypsin (ACT) and a2-macroglobulin (the latter of which is undetect-able with current immunoassays).21Christensson A Laurell CB Lilja H Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors.Eur J Biochem. 1990; 194: 755-763Crossref PubMed Scopus (599) Google Scholar, 22Lilja H Christensson A Dahlén U Matikainen M-T Nilsson O Pettersson K et al.Prostate-specific antigen in serum occurs predominantly in complex with a,-antichymotrypsin.ClinChem. 1991; 37: 1618-1625Google Scholar, 23Stenman U-H Leinonen J Alfthan H Rannikko S Tuhkanen K Alfthan O A complex between prostate-specific antigen and a,-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; 51: 222-226PubMed Google Scholar, 24Christensson A Björk T Nilsson O Dahlén U Matikainen M Cockett ATK et al.Serum prostate specific antigen complexed to al-antichymotrypsin as an indicator of prostate cancer.JUrol. 1993; 150: 100-105Google Scholar Total PSA is a combination of all immunodetectable forms in serum, primarily free PSA and PSA-ACT, even though trace amounts of complexes with protein C inhibitor, oCj-antitrypsin, and inter-alpha-trypsin inhibitor have been reported.36McCormack RT Rittenhouse HG Finlay JA Sokoloff RL Wang TJ Wolfert RL et al.Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era.Urology. 1995; 45: 729-744Abstract Full Text PDF PubMed Scopus (284) Google Scholar The complexed form between PSA and ACT is the predominant form in the serum, and the noncomplexed or free form is present in a smaller fraction22Lilja H Christensson A Dahlén U Matikainen M-T Nilsson O Pettersson K et al.Prostate-specific antigen in serum occurs predominantly in complex with a,-antichymotrypsin.ClinChem. 1991; 37: 1618-1625Google Scholar (Table 2).Table 2Molecular Forms of Prostate-Specific Antigen*PSA = prostate-specific antigen.Modified from McCormack and associates.36McCormack RT Rittenhouse HG Finlay JA Sokoloff RL Wang TJ Wolfert RL et al.Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era.Urology. 1995; 45: 729-744Abstract Full Text PDF PubMed Scopus (284) Google Scholar By permission.Formal nameCommon nameDescriptionTotal PSAt-PSAAll immunodetectable forms in serum, primarily f-PSA and PSA-ACTFree PSAf-PSANoncomplexed PSA; may be proteolytically active or inactive in seminal fluid, only inactive in serumPSA complexesPSA-ACTPSA covalently bound to α1-antichymotrypsin inhibitor; synonymous with PSA complex; major immunodetectable form in serumPSA-MGPSA covalently linked and encapsulated by cc2-macroglobulin; not detected in immunoassays; synonymous with occult PSAPSA-PCIPSA covalently bound to protein C inhibitor; minor component in seminal fluid; not detected in serumPSA-ATPSA covalently bound to α1-antitrypsin; trace component in serumPSA-ITPSA covalently bound to inter-alpha-trypsin inhibitor; trace component in serum* PSA = prostate-specific antigen. Open table in a new tab Preliminary investigations have illustrated the potential benefits of using free or complexed PSA (or their proportion to total PSA) to enhance the clinical utility of PSA in the early detection of prostate cancer. In 1991, Stenman and colleagues23Stenman U-H Leinonen J Alfthan H Rannikko S Tuhkanen K Alfthan O A complex between prostate-specific antigen and a,-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; 51: 222-226PubMed Google Scholar demonstrated that PSA complexed to ACT was higher in patients with prostate cancer than in patients with benign disease. They proposed that the complexed-to-total PSA proportion could discriminate between benign and malignant prostate disease and eliminate one-half of false-positive results (“negative” biopsies). These findings were confirmed subsequently by Christensson and coworkers.24Christensson A Björk T Nilsson O Dahlén U Matikainen M Cockett ATK et al.Serum prostate specific antigen complexed to al-antichymotrypsin as an indicator of prostate cancer.JUrol. 1993; 150: 100-105Google Scholar These investigators, however, suggested that the free-to-total proportion or percent free PSA, which is lower in patients with cancer, was a more sensitive or accurate means of discriminating between benign and malignant prostate disease. Using a percent free PSA cutpoint of 0.18, Christensson and associates reported an increase in specificity from 55 to 73% with minimal decrease in sensitivity. The major shortcomings of these studies were the relatively small number of patients and the inclusion of patients with a wide range of PSA values. Most investigations of percent free PSA have included patients with minimally increased PSA values and have focused on the ability of percent free PSA to eliminate negative prostate biopsies (improve specificity). The definition of a minimally increased PSA level has been arbitrarily determined, however, ranging from 4.1 ng/mL to 10.0 or even 20.0 ng/mL. In addition, percent free PSA may also be able to improve cancer detection (sensitivity) in patients with PSA values in the normal range (less than 4.0 ng/mL). Therefore, a logical first step would be to define an optimal range of total PSA for the use of percent free PSA (a reflex range). Indeed, several investigators have determined that percent free PSA is not useful for the whole range of PSA.26Luderer AA Chen YT Soriano TF Kramp WJ Carlson G Cuny C et al.Measurement of the proportion of free to total prostate-specific antigen improves diagnostic performance of prostate-specific antigen in the diagnostic gray zone of total prostate-specific antigen.Urology. 1995; 46: 187-194Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 37Klee GG Lerner SE Jacobsen SJ Bergstralh EJ Lilja H Pettersson K et al.Predictive power of free:total PSA ratio is not superior to total PSA in the diagnosis of prostate cancer in the community setting [abstract].JUrol. 1996; 155: 371AGoogle Scholar We recently conducted an investigation to define this optimal “reflex range.”38Vashi AR Wojno KJ Henricks W England BA Vessella RL Lange PH et
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