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Total, Complexed, and Free PSA Forms and Human Glandular Kallikrein 2
Abstract
In the United States, extensive use of prostate-specific antigen (PSA) for early detection of prostate cancer prostate cancer was responsible for a steady increase in the incidence of clinically and pathologically localized prostate cancer for more than a decade, with the incidence of locally advanced or metastatic disease steadily declining (1). The massive impact of PSA on the presentation of prostate cancer has caused concerns of overdetection and initiation of unnecessary treatment for so-called clinically insignificant prostate cancer. Recently, a decrease in prostate cancer incidence was noted, and today the incidence is only minimally higher than that seen in the pre-PSA era (2), suggesting that PSA is effective as a screening tool. An effective screening tool will increase the detection of a certain disease; however, the incidence should decrease over time, if significant disease is detected through that screening method. If, however the incidence does not decline, it is possible that insignificant disease may be detected.
To evaluate the accuracy of the TRIMprob in the diagnosis of prostate neoplasm.
Consecutive patients referred for prostate biopsy were prospectively enrolled. Patients had history taken, physical examination by digital rectal examination (DRE) of the prostate, assessment of total and free serum prostate-specific antigen (PSA) levels, prostate transrectal ultrasonography (TRUS), and TRIMprob test. Indications for prostate biopsy included one or more of the following conditions: total serum PSA levels of 4.0 ng/mL or more, free/total serum PSA ratio of 0.18 or less, positive results on DRE, and suspicious findings on TRUS. Twelve-core, TRUS-guided biopsies were performed with local anesthesia. A blinded investigator performed the TRIMprob test; the lowest value of the signal at 465 MHz was looked for and recorded, although data of the electromagnetic signal at 930 and 1295 MHz were also recorded.
One hundred eleven patients (aged 64.9 +/- 8.1 years, mean +/- standard deviation), enrolled between November 2004 and August 2005, were analyzed. Total serum PSA level was 8.4 +/- 3.6 ng/mL, and free/total serum PSA ratio was 0.15 +/- 0.7. TRIMprob sensitivity for the diagnosis of prostate cancer was 0.86%; specificity and positive and negative predictive values were 0.60 and 0.88; accuracy was 72%. TRIMprob accuracy outperformed any other diagnostic parameter considered, including the rule of chance. The association of TRIMprob and DRE offered a sensitivity and a negative predictive value of 0.86% or greater.
TRIMprob had the highest accuracy rate, among all other tests, for the diagnosis of prostate cancer. Electromagnetic detection with the TRIMprob test seems to be a promising technology and a useful additional tool for the early detection of prostate cancer.
Context:
The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use.
Objective:
To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied.
Design:
Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif).
Setting:
Seven nationwide university medical centers.
Participants:
A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis.
Main outcome measures:
A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients.
Results:
The percentage of free PSA may be used in 2 ways: as a single cut-off (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P < .001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL.
Conclusions:
Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice.
We have studied the forms of prostate-specific antigen (PSA) in serum of patients with prostatic cancer and benign prostatic hyperplasia. Fractionation of serum by gel filtration and assay of the fractions for PSA showed that a considerable part of the PSA immunoreactivity in serum consisted of complexes that were larger than PSA. The complexes were assayed by time-resolved immunofluorometric assays based on an antibody against PSA on the solid phase and europium-labeled antibodies against various protease inhibitors as indicator antibodies. In addition to its monomeric form, PSA was found to occur in complex with alpha 1-antichymotrypsin. The proportion of the alpha 1-antichymotrypsin complex was a major form of PSA and it increased with increasing PSA concentrations, being over 85% at PSA levels exceeding 1000 micrograms/liter. A complex with alpha 1-protease inhibitor was also observed in serum of patients with prostatic cancer and very high levels of PSA. Complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor were detected, but their concentrations were low and similar in sera of cancer patients, normal men, and normal women, suggesting that they were not prostate derived. Commercial immunoradiometric assays for PSA were found to measure free PSA and its complexes with alpha 1-antichymotrypsin but not the complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor. The proportion of the PSA-alpha 1-antichymotrypsin complex was higher in patients with prostatic cancer than in those with benign hyperplasia. Therefore, assay of the complex had a higher sensitivity for cancer than assay of total PSA immunoreactivity.
Immunologic measurements of the serum concentration of prostate-specific antigen (PSA), an abundant prostatic-secreted serine proteinase, are frequently used to monitor patients with prostate cancer, though it has not been ascertained whether this immunoreactivity represents a PSA zymogen, the active proteinase, or PSA complexed to extracellular proteinase inhibitors. To characterize the PSA immunoreactivity in serum, we used monoclonal antibodies produced against PSA and a polyclonal rabbit IgG against alpha 1-antichymotrypsin in the design of three noncompetitive PSA assays: assay T, which detected PSA both when present as the active proteinase and when complexed to alpha 1-antichymotrypsin; assay F, which recognized the active proteinase but most poorly detected PSA complexed to alpha 1-antichymotrypsin; and assay C, which was specific for PSA complexed to alpha 1-antichymotrypsin. We used the three assays to measure PSA immunoreactivity in 64 patients' sera and in the effluent after gel chromatography of sera from four patients. This identified an 80- to 90-kDa complex between PSA and alpha 1-antichymotrypsin as the predominant fraction of the PSA immunoreactivity in blood plasma; an immunoreactive 25- to 40-kDa compound was the minor fraction.
To isolate a human glandular kallikrein gene, a human genomic library was screened with a probe made from a mouse kallikrein cDNA (pMK-1). Overlapping clones were obtained and nucleotide sequence determination showed that they together contained a human glandular preprokallikrein gene, hGK-1, of 5.2 kb. The gene encoded a unique preproprotein of 261 amino acids. The sequence of the mature 237-amino-acid protein had 66% homology with the sequence predicted for human kallikrein synthesized in the pancreas, kidney, and salivary gland. Moreover, it had even stronger homology (78%) with human prostate-specific antigen. The latter lacks an aspartic acid residue essential for kallikrein-specific cleavage, whereas the sequence of this new protein had all of the attributes needed to confer kallikrein-like specificity. Southern blotting indicated that the number of glandular kallikrein genes in man could be limited to three, a situation very different from mouse and rat, which each have a large multigene family. Furthermore, unlike kallikrein genes in the mouse, hGK-1 was not closely linked to other human kallikrein genes. In other respects the structure of the human kallikrein gene resembled that in mouse: coding sequences in the five exons were organized similarly, homology was higher with other members of the kallikrein gene family in the same species, and the three key amino acid residues required by serine proteases for their catalytic activity, together with the residue that confers kallikrein-specific cleavage, were conserved and located on different exons. Thus, if hGK-1 is expressed, its product represents a new, and possibly the only other enzyme with true kallikrein-like specificity in man.
Generation of 15 monoclonal antibodies (MAbs) allowed construction of epitope maps and specific two-site immunofluorometric assays for free prostate-specific antigen (PSA) and PSA complexed with alpha 1-antichymotrypsin (ACT). Close correlation of PSA concentrations obtained with the use of different assays of free PSA suggested extensive similarity in immunodetection of free PSA in serum. Assays of the PSA-ACT complex overestimated the concentration of PSA-ACT in serum because of nonspecific adsorbance of ACT or cathepsin G-complexed ACT to the solid phase. This interference was substantially decreased in the presence of heparin. In studying the stability of purified PSA and PSA-ACT complexes formed in vitro, we found that the free PSA was stable during storage for 4 weeks at 35 degrees C, whereas PSA-ACT complexes largely dissociated in these conditions. The instability of PSA-ACT complexes was counteracted by storage at low temperatures, by adjusting the pH of the storage buffer between 6.8 and 7.4, and through addition of 100-1000-fold molar excess of native ACT. The ease of calibration and the accuracy of free PSA assays in comparison with assays of the PSA-ACT complex suggest that measurements of free to total PSA most accurately reflect the inverse of the proportion of PSA complexed to ACT in serum.
The prostate cancer detection rate from screening by digital rectal examination and tactilely guided prostate biopsy is approximately 1.7%. Among 1,807 men a detection rate of 14.6% was achieved in a clinical urological practice by physician-conducted prostate ultrasonography, digital rectal examination and determination of serum prostate specific antigen. Results are presented in 5-year increments as well as for the group as a whole. The possible benefit to be derived from an improved detection rate is undetermined. Recommendations are made regarding the clinical use of these diagnostic modalities.
The prostate specific antigen (PSA) level has become an important but imperfect means of detecting prostatic carcinoma. PSA index (serum PSA normalized to estimated gland volume) has been suggested to improve the performance characteristics of PSA alone. In an attempt to confirm this observation, we compared serum PSA alone to the PSA index in 218 men undergoing systematic random prostatic needle biopsy. Total gland PSA index as well as nontransition zone PSA index were calculated using several constants for the estimated contribution to the serum PSA from the transition zone. The Mann-Whitney nonparametric analysis was performed to account for differences in variances within the data set.
Objective:
To combine the clinical data from 3 academic institutions that serve as centers of excellence for the surgical treatment of clinically localized prostate cancer and develop a multi-institutional model combining serum prostate-specific antigen (PSA) level, clinical stage, and Gleason score to predict pathological stage for men with clinically localized prostate cancer.
Design:
In this update, we have combined clinical and pathological data for a group of 4133 men treated by several surgeons from 3 major academic urologic centers within the United States. Multinomial log-linear regression was performed for the simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement. Bootstrap estimates of the predicted probabilities were used to develop nomograms to predict pathological stage. Additional bootstrap analyses were then obtained to validate the performance of the nomograms.
Patients and settings:
A total of 4133 men who had undergone radical retropubic prostatectomy for clinically localized prostate cancer at The Johns Hopkins Hospital (n=3116), Baylor College of Medicine (n=782), and the University of Michigan School of Medicine (n=235) were enrolled into this study. None of the patients had received preoperative hormonal or radiation therapy.
Outcome measures:
Simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement using updated nomograms.
Results:
Prostate-specific antigen level, TNM clinical stage, and Gleason score contributed significantly to the prediction of pathological stage (P<.001). Bootstrap estimates of the median and 95% confidence interval of the predicted probabilities are presented in the nomograms. For most cells in the nomograms, there is a greater than 25% probability of qualifying for more than one of the pathological stages. In the validation analyses, 72.4% of the time the nomograms correctly predicted the probability of a pathological stage to within 10% (organ-confined disease, 67.3%; isolated capsular penetration, 59.6%; seminal vesicle involvement, 79.6%; pelvic lymph node involvement, 82.9%).
Conclusions:
The data represent a multi-institutional modeling and validation of the clinical utility of combining PSA level measurement, clinical stage, and Gleason score to predict pathological stage for a group of men with localized prostate cancer. Clinicians can use these nomograms when counseling individual patients regarding the probability of their tumor being a specific pathological stage; this will enable patients and physicians to make more informed treatment decisions based on the probability of a pathological stage, as well as risk tolerance and the values they place on various potential outcomes.
Purpose:
Age-specific prostate specific antigen (PSA) references ranges have been suggested to account for the age-dependent nature of the serum PSA concentration. It has been hypothesized that reference ranges of 0 to 2.5 ng./ml.serum PSA (40-49 years), 0 to 3.5 ng./ml. (50-59 years), 0 to 4.5 ng./ml. (60 to 69 years) and 0 to 6.5 ng./ml. (70 to 79 years) would detect fewer (potentially insignificant) prostate cancers in older men and more (potentially curable) cancers in younger men.
Materials and methods:
To investigate the pathological stage of tumors that would be affected by the use of age-specific PSA references ranges, we reviewed the medical records for 4,597 men with clinically localized (stage T1c, T2, or T3a) prostate cancer, with an average age of 62 +/- 7 years (range 38 to 76), who underwent radical prostatectomy between 1984 and 1994 at our institutions. Favorable pathological results were defined as organ-confined disease or capsular perforation with a Gleason score of less than 7, and unfavorable pathological results were defined as capsular perforation with a Gleason score of 7 or more, seminal vesicle invasion or lymph node involvement.
Results:
Overall, 18% of the men had PSA levels less than the standard PSA reference range (4.0 ng./ml.) compared to 22% when using the age-specific ranges. There were 74 more cancers detected in men younger than 60 years with the use of age-specific ranges, of which 81% had favorable pathological results. Among the men 60 years or older, 191 of 252 cancers (76%) not detected by using age specific ranges less than 3% were also stage T1c and 95% of these undetected T1c cancers were of favorable pathological status. Of those cancers not detected in older men with the age-specific ranges were of favorable pathological status. Of those cancers not detected in older men with age-specific ranges less than 3% were also stage T1c and 95% of these undetected T1c cancers were of favorable pathological status. Age-specific PSA reference ranges increased the potential for detection of prostate cancer by 18% in the younger men and decreased the detection by 22% in the older men.
Conclusions:
Among these men with clinically localized prostate cancer, age specific PSA references ranges increased the detection of more potentially curable tumors in young men and decreased the detection of less advanced tumors in the older men compared to the standard reference range of 4.0 ng./ml. Among older men with nonpalpable (stage T1c) tumors age-specific PSA references ranges would have detected fewer tumors. However, 95% of these "missed" tumors would have had favorable pathological findings.
Objective.
—To combine the clinical data from 3 academic institutions that serve as centers of excellence for the surgical treatment of clinically localized prostate cancer and develop a multi-institutional model combining serum prostate-specific antigen (PSA) level, clinical stage, and Gleason score to predict pathological stage for men with clinically localized prostate cancer.Design.
—In this update, we have combined clinical and pathological data for a group of 4133 men treated by several surgeons from 3 major academic urologic centers within the United States. Multinomial log-linear regression was performed for the simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement. Bootstrap estimates of the predicted probabilities were used to develop nomograms to predict pathological stage. Additional bootstrap analyses were then obtained to validate the performance of the nomograms.Patients and Settings.
—A total of 4133 men who had undergone radical retropubic prostatectomy for clinically localized prostate cancer at The Johns Hopkins Hospital (n=3116), Baylor College of Medicine (n=782), and the University of Michigan School of Medicine (n=235) were enrolled into this study. None of the patients had received preoperative hormonal or radiation therapy.Outcome Measures.
—Simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement using updated nomograms.Results.
—Prostate-specific antigen level, TNM clinical stage, and Gleason score contributed significantly to the prediction of pathological stage (P<.001). Bootstrap estimates of the median and 95% confidence interval of the predicted probabilities are presented in the nomograms. For most cells in the nomograms, there is a greater than 25% probability of qualifying for more than one of the pathological stages. In the validation analyses, 72.4% of the time the nomograms correctly predicted the probability of a pathological stage to within 10% (organ-confined disease, 67.3%; isolated capsular penetration, 59.6%; seminal vesicle involvement, 79.6%; pelvic lymph node involvement, 82.9%).Conclusions.
—The data represent a multi-institutional modeling and validation of the clinical utility of combining PSA level measurement, clinical stage, and Gleason score to predict pathological stage for a group of men with localized prostate cancer. Clinicians can use these nomograms when counseling individual patients regarding the probability of their tumor being a specific pathological stage; this will enable patients and physicians to make more informed treatment decisions based on the probability of a pathological stage, as well as risk tolerance and the values they place on various potential outcomes.
Objective.
—To evaluate the validity of prostate-specific antigen (PSA) in identifying men who subsequently were or were not clinically diagnosed with prostate cancer, assess optimal test cutoff, measure lead time, and estimate relative risks (RRs) associated with discrete PSA levels.
Design.
—Nested case-control study of men providing plasma samples before a 10-year follow-up.
Setting.
—The Physicians' Health Study, an ongoing randomized trial that enrolled 22071 men aged 40 to 84 years in 1982.
Participants.
—A total of 366 men (cases) diagnosed with prostate cancer and 1098 men (three controls per case), matched by age, randomly selected from all cohort members at risk at the time of case diagnosis.
Main Outcome Measures.
—Sensitivity and specificity for each year of followup and for aggressive and nonaggressive cancers separately.
Results.
—At a cutoff of 4.0 ng/mL, sensitivity for the entire 10-year follow-up was 46% for total cases. Sensitivities for detection of total, aggressive, and nonaggressive cancers occurring in the first 4 years were 73%, 87%, and 53%. Overall, specificity was 91% and changed little by year of follow-up. Optimal validity was achieved at a cutoff of 3.3 ng/mL. Estimated mean lead time for all cancers was 5.5 years. Only 40% of cancers detected more than 5 years from baseline were nonaggressive. Compared with men with PSA levels less than 1.0 ng/mL, those with PSA levels between 2.0 and 3.0 ng/mL had an RR of 5.5 (95% confidence interval, 3.7 to 9.2).
Conclusions.
—A single PSA measurement had a relatively high sensitivity and specificity for detection of prostate cancers that arose within 4 years. Prostatespecific antigen values less than the usual cutoff were associated with substantial increases in risk compared with the lowest levels. Final evaluation of PSA screening must also consider cost and the ability of current treatments to improve the prognosis of screen-detected cases.(JAMA. 1995;273:289-294)
Objective.
—To determine whether prostate-specific antigen (PSA)—based screening alters the proportion of organ-confined prostate cancers detected.Design.
—A prospective, nonrandomized, serial PSA-based screening trial (follow-up from 6 to 37 months), and a concurrent comparison group.Setting.
—Genera community outpatient screening program based at a university center.Patients.
—The study group consisted of 10251 men aged 50 years and older (mean and median age, 63 years; mean and median age of patients who underwent biopsies, 66 years) who presented to a prostate cancer screening program and consented to phlebotomy. The comparison group consisted of 266 concurrently studied private patients in the same age range (mean and median age, 68 years) who were referred for prostatic ultrasonography and biopsy because of an abnormal digital rectal examination (DRE).Main Outcome Measure.
—Proportion detected with clinically or pathologically advanced prostate cancer.Results.
—The men were divided into three groups: the comparison group, the initial PSA-based screening group, and the serial PSA-based screening group. The proportions of prostate cancers detected that were clinically or pathologically advanced were as follows: comparison group, 57% (27/47); initial PSA-based screening group, 37% (91/244); and serial PSA-based screening group, 29% (37/ 129). Screened patients had a lower proportion of advanced cancers than the comparison group (χ2 [2]=12.3; P=.002); this advantage was observed principally in patients younger than 70 years. Surgical staging revealed that the cancer was microscopically focal and well differentiated (possibly latent cancer) in 2.5% (1/40) of the nonscreened group, 2.9% (7/244) of the initially screened group, and 7.8% (10/129) of the serially screened group (generalized Fisher's Exact Test, P=.08).Conclusion.
—Screening based on PSA identifies some men with prostate cancer who have a significantly increased proportion of organ-confined tumors compared with those detected through evaluation for an abnormal DRE alone.(JAMA. 1993;270:948-954)
Objective.
—To determine the detection rate of prostate cancer in a screening population of men with prostate-specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies.Design.
—A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations.Setting.
—University medical center.Subjects.
—A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate.Main Outcome Measures.
—Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA.Results.
—Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low-grade or moderately low-grade tumors (possibly harmless). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy.Conclusions.
—There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.
Objective To determine whether serum levels of the prostate-specific antigen-α1-antichymotrypsin complex (PSA-ACT) and its density (ACTD) in patients scheduled to undergo radical prostatectomy for clinically localized prostate cancer can predict organ-confined vs extraprostatic disease.
Patients and methods Serum samples were obtained from 62 patients with clinically localized prostate cancer before they underwent radical prostatectomy. PSA and PSA-ACT were measured using immunofluorometric techniques with different monoclonal antibodies against PSA and ACT, respectively. Furthermore, the PSA and PSA-ACT densities of the whole prostate (PSAD and ACTD, respectively) were calculated. The relationships of serum PSA, PSA-ACT, PSAD, ACTD and the pathological stage of the prostatectomy specimens were analysed.
Results The disease was organ-confined or extraprostatic in 30 and 32 men, respectively. In men with organ-confined cancer, the mean PSA and PSA-ACT levels were significantly lower than in those with extraprostatic disease. Furthermore, there were significantly higher mean PSAD and ACTD levels in men with extraprostatic than with organ-confined disease. There were also significant differences in PSA, PSA-ACT, PSAD and ACTD levels at each pathological stage, whereas there was no significant association between these variables and the Gleason score. Receiver-operating characteristic curve analysis for detecting organ-confined disease showed that PSA-ACT and ACTD had a larger area under the curve than PSA and PSAD, respectively, but these differences were not significant. Furthermore, PSA-ACT and ACTD provided significantly better sensitivity for detecting organ-confined disease than PSA and PSAD, respectively.
Conclusions Measuring PSA-ACT and ACTD may improve the preoperative evaluation of patients scheduled to undergo radical prostatectomy, because these factors better differentiate extraprostatic from organ-confined disease than PSA and PSAD.
Background We studied the clinical significance of serum prostate-specific antigen bound to α1-antichymotrypsin (PSA-ACT) values determined with a newly developed enzyme immunoassay.
Methods Serum PSA-ACT values were determined in a total of 652 sera. Clinical utility for the diagnosis of prostate cancer was compared to that of Tandem-R PSA and y-seminoprotein (μgm- Sm). The new enzyme immunoassay is based on the use of the Stanford reference as an international standard for PSA assays.
Results Serum PSA-ACT values ranged from less than 0.10 to 1.4ng/mL in healthy males (n = 100) while values in patients with benign prostatic hyperplasia (n = 1 55) averaged 3.4 ± 3.8ng/mL (mean ± SD). In patients with prostate cancer, serum PSA-ACT values increased significantly with progression of the clinical stage and there were statistically significant differences between benign prostatic hyperplasia and each stage of prostate cancer except for stage A. Using BPH levels as controls (4.8ng/mL for PSA-ACT, 7.2ng/mL for PSA, 3.8ng/mL for y-Sm, and 2.4ng/mL for thecomplexed/free PSA ratio of PSA-ACT/μtgM-Sm), specificity was 80%. The sensitivity of prostate cancer detection was 79% for PSA-ACT, 77% for PSA, 57% for γ-Sm, and 46% for the ratio between PSA-ACT/γ-Sm.
Conclusion Although the determination of serum PSA-ACT showed essentially the same utility as that of PSA for the diagnosis of prostate cancer, PSA-ACT may allow prediction of the clinical stage. The PSA-ACT assay may therefore replace PSA in the detection of prostate cancer.
Objectives
To study the in vitro stability of free and complexed forms of prostate specific antigen (PSA) in blood samples in order to establish guidelines for specimen handling, in particular for the clinical utility of the analysis of percentage free PSA.
BACKGROUND
Data on 349,154 prostate cancer cases diagnosed since 1986 have been entered to the American College of Surgeons National Cancer Data Base (NCDB). Previous annual reports have examined subsets of these data. The present report highlights major trends in the presentation and treatment of prostate cancer in the United States evident from longitudinal analyses of the entire data.METHODSNCDB data are collected following a computerized, standard format. Hospital participation is voluntary.RESULTSSince the first year of data collection, the number of participating hospitals has increased from 496 to 996 and the number of prostate cancer patients reported to the NCDB increased from 19,531 to 84,408. The proportion of men diagnosed at ages younger than 70 years increased from 37.8% in 1986 to 46.9% in 1993. Completeness of reporting stage of disease and tumor grade has improved. The proportions of both the earliest (American Joint Committee on Cancer [AJCC] Stage Groups 0 and I) and the most advanced (AJCC Stage Group IV) stages declined. The proportion of Grade 2 (moderately differentiated) tumors increased from 38.6% in 1986 to 57.5% in 1993. The proportion of AJCC Stage II prostate cancer increased from 19% in 1986 to 48.4% in 1993. The proportion of patients treated by prostatectomy increased from 9.9% in 1986 to 29.2% in 1993. The proportion of patients receiving no cancer directed treatment declined from 41.8% in 1986 to 21.6% in 1993. Less change was observed in the use of radiation and hormonal treatments.CONCLUSIONS
These data show that the clinical patterns of prostate cancer have changed markedly in recent years. Cancer 1996;77:2162-6.
Objective To determine whether the age-specific reference ranges for serum prostate-specific antigen (PSA) concentration generated for white men are applicable to other races.
Patients and methods Three-hundred and thirty-five healthy lapanese men, aged 40–79 years, residing in the small fishing village of Shimamaki-mura, Japan, agreed to enter this prospective, community-based study. All underwent a detailed clinical evaluation that included a serum PSA determination, a digital rectal examination and a transrectal ultrasound. Two-hundred and eighty-six (85%) completed the prostatic evaluation and had no evidence of prostate cancer by any one of the three diagnostic tests; these men formed the study population on which all analyses were performed.
Results The serum PSA concentration correlated directly with patient age (r = 0.33; P<0.001) and prostatic volume (r=0.57; P<0.001). PSA density (PSAD) also was directly proportional to age (r= 0.30; P<0.001). Adjusting for age, the serum PSA concentration was lower for Japanese men than for white men (P<0.001). Thus, the recommended age-specific reference ranges (95th percentile) for serum PSA for Japanese were lower as well: 0.0–2.0 ng/mL for 40–49 years; 0.0–3.0 ng/mL for 50–59 years; 0.0–4.0 ng/mL for 60–69 years; and 0.0–5.0 ng/mL for 70–79 years. Based on transrectal ultrasound-volume determinations, the lower serum PSA concentrations in Japanese men are due in large part to their smaller prostate glands as compared with white men (P<0.001).
Conclusions These findings confirm the earlier observations that serum PSA, prostatic volume and PSAD are age-dependent. However, because of physiological differences among the two races, partly due to the size of the prostate gland, the age-specific reference ranges for serum PSA are lower for Japanese men than for white men. Because of these racial differences, it is now crucial to conduct a similar investigation among black men.
Purpose:
Approximately 25% of radical prostatectomies performed for stage T1c disease show potentially insignificant prostate cancer. We previously reported the use of serum prostate specific antigen (PSA) density and needle biopsy findings to predict potentially insignificant cancer. We now evaluate whether using free/total serum PSA levels along with needle biopsy findings can better predict tumor significance.
Materials and methods:
We studied 163 radical prostatectomy specimens of stage T1c prostate cancer in which free/total serum PSA levels were determined. Free/total serum PSA levels were measured with Tandem-MP PSA assays. Insignificant prostate cancers were organ confined with tumor volumes less than 0.5 cc and Gleason score less than 7. Advanced tumors were either Gleason score 7 or greater, established extraprostatic extension with positive margins, or positive seminal vesicles or lymph nodes. Other cases were considered as moderate tumor. Moderate and advanced tumors were considered significant.
Results:
Of the tumors 30.7% were insignificant, 49.7% moderate and 19.6% advanced. The best model to predict preoperatively insignificant tumor was a free/total PSA of 0.15 or greater and favorable needle biopsy findings (less than 3 cores involved, none of the cores with greater than 50% tumor involvement and Gleason score less than 7). Using this model of the 18 tumors predicted to be insignificant 17 were insignificant for a positive predictive value of 94.4%. Of the 145 cases that were predicted to be significant 112 were correctly predicted for a negative predictive value of 77.2%. There was only 1 tumor predicted to be insignificant which was classified as moderate. No tumor predicted to be insignificant was advanced.
Conclusions:
In conjunction with needle biopsy findings, free/total PSA levels accurately predict insignificant tumor in stage T1c disease.
The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer.
In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10.
Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease.
These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.
Kallikreins are involved in the posttranslational processing of a number of specific polypeptide precursors. Previously, human glandular kallikrein (hGK-1) mRNA has been identified in the prostate; however, the hGK-1 protein has not been identified and characterized. Therefore, its physiologic function in the prostate is not known. In this study, we have isolated a full-length hGK-1 cDNA from a human adenocarcinoma cell line, LNCaP. In vitro translation experiments demonstrated that the molecular size of the hGK-1 protein generated from this cDNA is similar to that of prostate-specific antigen (PSA), a protein which is produced exclusively in the prostate. In situ hybridization with a hGK-1-specific oligonucleotide probe (77 bases), which can differentiate hGK-1 mRNA from PSA mRNA, demonstrated the hGK-1 mRNA to be located in the prostate epithelium. The hGK-1 mRNA was colocalized with PSA mRNA in prostatic epithelia. Moreover, in situ hybridization studies revealed that the level of hGK-1 mRNA in human benign prostatic hyperplasia tissues is approximately half that of PSA mRNA. Furthermore, we have demonstrated that hGK-1 mRNA is under androgenic regulation in LNCaP cells. Time course analysis revealed that hGK-1 mRNA levels increased significantly at 5 h of mibolerone treatment and reached maximal levels by 9 h. In addition, hGK-1 mRNA levels were increased by dihydrotestosterone, but not by dexamethasone or diethylstilbestrol treatments. Flutamide, a nonmetabolized anti-androgen, repressed the androgenic effects. These studies suggest that expression of hGK-1 mRNA is regulated by androgen via the androgen receptor.
Prostate specific antigen (PSA) is an extremely valuable tumor marker. However, its use in detection is limited by its low positive and negative predictive values. The ability of serum PSA to distinguish between benign and malignant prostatic conditions is particularly poor in the intermediate range of 4.1 and 10 ng./ml. by the Hybritech assay. We used transrectal ultrasound determined prostate volumes in a well characterized population of 533 men to form a serum PSA/prostate volume ratio called prostate specific antigen density (PSAD). The prevalence of cancer in the entire population was 18.4%. Discriminant analysis according to negative or positive outcome allowed for the construction of nomograms, which resulted in a PSAD defined cancer risk ranging from 3 to 100%. Predictive value nomograms created from PSAD may allow for a more individualized approach to evaluation of patients with intermediate levels of Hybritech serum PSA.
To evaluate the usefulness of serum prostate specific antigen in the preoperative staging of prostate cancer we examined tumor volume and differentiation, as well as benign prostatic hyperplasia volume to determine their influence on serum antigen levels. Serum prostate specific antigen was measured in 350 men with clinically localized prostate cancer and preoperatively in 72 men with documented benign prostatic hyperplasia. Although the mean antigen levels increased with advancing pathological stage, the usefulness of prostate specific antigen to predict pathological stage for an individual patient was limited: 1 of 102 men (0.9%) with prostate specific antigen levels of less than 2.8 ng./ml. had positive lymph nodes and 5 of 5 men with levels of greater than 100 ng./ml. had either seminal vesicle or lymph node involvement. However, for the majority of men (greater than 70%) with prostate specific antigen values between these 2 extremes the antigen levels did not accurately predict pathological stage. Because serum prostate specific antigen levels correlated with morphometrically determined tumor volume (r equals 0.535, p less than 0.01) they should, in fact, be predictive of pathological stage. However, most men with prostate cancer also have varying degrees of benign prostatic hyperplasia tissue in the gland producing prostate specific antigen. We have found that serum prostate specific antigen does not correlate with the volume of benign hyperplasia within the gland (r equals 0.21, p greater than 0.05). In addition, immunohistochemical studies have suggested that the lack of correlation between pathological stage and serum prostate specific antigen might be explained by a decrease in the production of antigen with increasing histological grade. Our findings of a negative correlation (r equals —0.37, p less than 0.01) between serum prostate specific antigen levels and Gleason score adjusted for tumor volume confirmed this suggestion.
The prostate cancer detection rate from screening by digital rectal examination and tactilely guided prostate biopsy is approximately 1.7%. Among 1,807 men a detection rate of 14.6% was achieved in a clinical urological practice by physician-conducted prostate ultrasonography, digital rectal examination and determination of serum prostate specific antigen. Results are presented in 5-year increments as well as for the group as a whole. The possible benefit to be derived from an improved detection rate is undetermined. Recommendations are made regarding the clinical use of these diagnostic modalities.
Presently, the standard staging evaluation of prostate cancer includes digital rectal examination, measurement of serum tumor markers and a radionuclide bone scan. To evaluate the ability of local clinical stage, tumor grade, serum acid phosphatase, serum prostatic acid phosphatase (PAP) and serum prostate specific antigen (PSA) to predict bone scan findings, a retrospective review of 521 randomly chosen patients (mean age 70 years, range 44 to 92 years) with newly diagnosed, untreated prostate cancer was performed.
Prostate-specific antigen (PSA) is one of the three most abundant prostatic-secreted proteins in human semen. It is a serine proteinase that, in its primary structure, manifests extensive similarities with that of the Arg-restricted glandular kallikrein-like proteinases. When isolated from semen by the addition of chromatography on aprotinin-Sepharose to a previously described procedure, PSA displayed chymotrypsin-like activity and cleaved semenogelin and the semenogelin-related proteins in a rapid and characteristic pattern, but had no trypsin-like activity. About one third of the purified protein was found to be enzymatically inactive, due to cleavage carboxy-terminal of Lys145. Active PSA formed SDS-stable complexes with alpha 1-antichymotrypsin, alpha 2-macroglobulin-analogue pregnancy zone protein. PSA formed inhibitory complexes with alpha 1-antichymotrypsin at a molar ratio of 1:1, a reaction in which PSA cleaved the inhibitor in a position identical to that reported from the reaction between chymotrypsin and alpha 1-antichymotrypsin. The formation of stable complexes between PSA and alpha 1-antichymotrypsin occurred at a much slower rate than that between chymotrypsin and alpha 1-antichymotrypsin, and at a similar or slightly slower rate than that between PSA and alpha 2-macroglobulin. When added to normal blood plasma in vitro, active PSA formed stable complexes both with alpha 2-macroglobulin and alpha 1-antichymotrypsin. This complex formation may be a crucial determinant of the turnover of active PSA in intercellular fluid or blood plasma in vivo.
We established the location and extent of complete capsule penetration by prostate cancer in 176 radical prostatectomy specimens and related these findings to cancer volume, location of positive surgical margins, and presence of nodal metastases or seminal vesicle (SV) invasion. Extent of capsule penetration, cancer volume, and positive nodes/SV were strongly intercorrelated. It could not be shown that capsule penetration was related to prognosis independently of its correlation with cancer volume. Twelve cubic centimeters was a critical cancer volume; above that, combinations of extensive capsule penetration, positive surgical margins, and positive nodes/SV were almost universal. In cancers under 12 cc, positive surgical margins were only moderately correlated with cancer volume; they often represented surgical resection into the capsule rather than a complication of capsule penetration by tumor and were most common at the apex, where dissection is most difficult. In non-transition zone cancers (148 cases), capsule penetration was most common posterolaterally, where nerves penetrate the capsule. In transition zone cancers (28 cases), capsule penetration was much less common and was located more anteriorly. Apical positive margins were also relatively common in transition zone cancers, but seminal vesicle invasion was never seen.
The usefulness of prostate specific antigen to predict final pathological stage was studied in 178 consecutive patients. Prostate specific antigen was determined preoperatively in all patients by a monoclonal immunoradiometric assay. All pathological specimens were examined for capsular penetration, seminal vesicle involvement and lymph node involvement. Prostate specific antigen correlated directly with capsular penetration (p less than 0.002), seminal vesicle involvement (p less than 0.02) and lymph node involvement (p less than 0.05). However the diagnostic accuracy of an elevated serum antigen level on an individual basis was only 55 per cent for capsular penetration and 50 per cent for seminal vesicle involvement and lymph node involvement.
We evaluated serum prostate specific antigen before and after radical prostatectomy. In 100 consecutive patients who underwent radical prostatectomy, preoperative prostate specific antigen levels tended to increase with the increasing severity of pathological stage. However, even at levels of greater than 10 ng. per ml. the positive and negative predictive values (78 and 61 per cent, respectively) of prostate specific antigen to predict extracapsular disease were not sufficient to make this test useful alone for staging. In theory, after radical prostatectomy prostate specific antigen should be zero if no remaining prostatic tissue is present. Tests of precision and analytical sensitivity in our laboratory using a commercial prostate specific antigen assay revealed that a value of 0.4 ng. per ml. or more is different from zero at a greater than 95 per cent confidence level. With this guideline we evaluated the meaning of prostate specific antigen levels 3 to 6 months after radical prostatectomy in 59 men. Among men whose prostate specific antigen level was less than 0.4 ng. per ml. only 9 per cent demonstrated recurrence as evidenced by the development of positive bone scan or progressively elevated prostate specific antigen levels within 6 to 50 months. Alternatively, in men whose 3 to 6-month prostate specific antigen level was 0.4 ng per ml. or more there was evidence of recurrence in 100 per cent within 6 to 49 months (p less than 0.0001). Progressively elevated (more than 0.4 ng. per ml.) prostate specific antigen levels preceded recurrence from 12 to 43 months in all 6 patients who had positive bone scans, while increasing prostate specific antigen levels since radical prostatectomy have continued from 9 to 65 months in the 11 patients who have no radiological evidence of recurrent disease to date. Prostatic acid phosphatase serum values after radical prostatectomy were not useful to predict persistent disease. Prostate specific antigen values 3 to 6 months after radical prostatectomy are a sensitive indicator of persistent disease after radical prostatectomy and often precede other evidence of this occurrence by many years. This fact may alter concepts about surgical results, and possibly shorten and sharpen clinical studies involving adjuvant therapy after radical prostatectomy.
Serum prostate specific antigen was determined (Yang polyclonal radioimmunoassay) in 102 men before hospitalization for radical prostatectomy. Prostate specimens were subjected to detailed histological and morphometric analysis. Levels of prostate specific antigen were significantly different between patients with and without a Gleason score of 7 or greater (p less than 0.001), capsular penetration greater than 1 cm. in linear extent (p less than 0.001), seminal vesicle invasion (p less than 0.001) and pelvic lymph node metastasis (p less than 0.005). Prostate specific antigen was strongly correlated with volume of prostate cancer (r equals 0.70). Bivariate and multivariate analyses indicate that cancer volume is the primary determinant of serum prostate specific antigen levels. Prostate specific antigen was elevated 3.5 ng. per ml. for every cc of cancer, a level at least 10 times that observed for benign prostatic hyperplasia.
This study was designed to compare the usefulness of the normal prostate-specific antigen (PSA) level and the age-referenced PSA level in a large screening study for early detection of prostate cancer.
A total of 21,078 subjects (aged 45 to 75 years) were participants in a 1-year prostate cancer screening project with PSA as the initial test. Of the volunteers, 1618 (8%) showed an elevated PSA level according to age-specific reference ranges, and using the normal PSA cutoff point (4.0 ng/mL), 1872 (9%) had elevated PSA levels between 4.0 and 6.5 ng/mL.
Biopsies in both groups were performed if the PSA level was elevated. We evaluated the effect on biopsy rate and cancer detection. A PSA cutoff point of 2.5 ng/mL in men 45 to 49 years old and a PSA cutoff point of 3.5 ng/mL in men 50 to 59 years old with normal digital rectal examination findings resulted in an 8% increase in the number of biopsies (66 of 778) and an 8% increase in organ-confined cancer detection. An increasing cutoff of 4.5 ng/mL in men 60 to 69 years old and 6.5 ng/mL in men 70 to 75 years old resulted in 21% fewer biopsies (205 of 983) and would have missed 4% of organ-confined tumors (8 of 220).
We conclude that the use of PSA age-specific reference ranges increases the detection of clinically important and organ-confined cancers in young men and decreases the number of biopsies in older men.
In 651 patients mapping of the prostate by 6 systematic sextant ultrasonography guided biopsies was performed without major side effects using the automatic biopsy gun. The histological findings provided data on patients with normal and abnormal prostates as determined by digital rectal examination. Only 3 of 72 nonurological patients (4%) with normal prostate specific antigen (PSA) levels of less than 4 ng./ml. had prostate cancer. Of the 259 patients with a firm prostate on digital rectal examination 105 (41%) had prostate cancer. For those with a PSA level of less than 4 and 4 ng./ml. or greater the positive biopsy rates were 13% and 58%, respectively. Of 56 patients with clinical stage B or C disease and a PSA level of less than 4 ng./ml. 20 (36%) had prostate cancer, compared to 155 of 187 (83%) with a PSA level of 4 ng./ml. or greater. Transrectal ultrasound was not helpful in screening for prostate cancer due to the low positive biopsy rate for hypoechoic lesions. However, among 175 patients with clinical stage B or C disease transrectal ultrasound identified 157 (90%) with prostate cancer.
An evaluation of longitudinal changes in PSA in men with and without prostate disease revealed that with age, the development of prostate disease is the most important factor influencing changes in PSA. Furthermore, the PSA changes with age are significantly different in men with and without prostate disease. The PSA velocity is greater in men with prostate cancer than in men with BPH and greater in men with prostate cancer and BPH than in men without any prostate disease. Thus, evaluation of PSA changes may help distinguish between men with prostate cancer and those without the disease. This idea will need to be confirmed prospectively. Finally, estimation of PSA doubling time from changes in PSA suggests that changes reflect prostatic growth. Therefore, PSA velocity could be of benefit in identifying men with prostate cancer that is destined to progress.
Prostate Specific Antigen (PSA) is the most accurate serum marker for cancer of the prostate. However, sensitivity and specificity are suboptimal, especially at the intermediate levels between 4.1 and 10.0 ng/ml (monoclonal). For intermediate PSA levels, prostate specific antigen density (PSAD) provides unique information regarding the need for biopsy and the likelihood of prostate cancer. This article summarizes the utility of PSAD in diagnosing and treating prostate cancer.
Protein C inhibitor (PCI), a serine-proteinase inhibitor first purified from human blood plasma, occurs at high concentrations (3–4 μM) in seminal fluid in both a high-molecular-mass and low-molecular-mass form. Immunochemical data have previously suggested that PCI in seminal plasma forms complexes with the most abundant serine proteinase in semen, prostate-specific antigen (PSA). To provide a structural characterization of the PCI target, immunodetected as PSA, a procedure was developed to isolate low-molecular-mass and high-molecular-mass-forms of PCI from seminal fluid. The high-molecular-mass form of PCI, recognized by monoclonal antibodies against PSA, was dissociated by alkaline treatment into the low-molecular-mass form of PCI and a 33-kDa protein identified as PSA by 25 conclusive steps of N-terminal sequence analysis. We developed a sensitive immunofluorometric assay (IFMA) to measure PCI-PSA complexes in body fluids and investigated the rate at which purified PSA may form complexes with purified PCI. Formation of complexes detected by this IFMA and the appearance of SDS-stable approximately 90-kDa complexes paralleled loss of PSA activity recorded with chromogenic substrates. The rate of complex formation was slow compared to that reported for PCI and activated protein C, but was enhanced up to sixfold in the presence of heparin. Less than 10% of the initial PSA activity remained after 3 h incubation with a sevenfold molar excess of PCI and in the presence of heparin.
To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandem-E or Tandem-R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 micrograms/l or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 micrograms/l, 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 micrograms/l or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.
The American Cancer Society-National Prostate Cancer Detection Project is a prospective, comparative study of a cohort of 2,999 men 55 to 70 years old not suspected on entry of having prostate cancer. A total of 164 prostate cancers is available from this project for analysis. A small proportion of tumors detected were advanced in terms of the clinical stage at diagnosis. Cancer detected by digital rectal examination tended to be more advanced than that found on the basis of only transrectal ultrasound or prostate specific antigen (PSA). A large proportion of patients received curative therapy involving radical prostatectomy in 67.1% and radiotherapy in 18.3%. Of 103 men presumed to have organ confined disease and treated by prostatectomy 64 (37.9%) actually had locally extensive cancer pathologically. PSA level and PSA density were associated with the detection of organ confined cancer but several advanced tumors had PSA levels in the normal range. Age referenced PSA, compared to conventional standards, demonstrated lower sensitivity to cancer with little improvement in specificity. The disease resulting from this multimodality detection effort represented a spectrum of pathological conditions. Further followup and evaluation are needed to determine whether these benefits are reflected in long-term mortality and survival experience.
Three tests are commonly used to diagnose prostate carcinoma to date: serum prostate specific antigen (PSA), digital rectal examination and transrectal ultrasonography. We evaluated these 3 tests in 1,001, 6-sector prostate needle biopsies to rule out prostate carcinoma. Of the biopsies 253 (25.3%) revealed prostate cancer. As a single test, PSA was superior to digital rectal examination or transrectal ultrasonography in predicting cancer in this patient population using difference of proportions tests. Receiver operating characteristic analysis also showed PSA to be the superior test. The combinations of PSA plus transrectal ultrasonography and PSA plus digital rectal examination were superior to digital rectal examination plus transrectal ultrasonography. We found cancer in 35 of 188 patients (18.6%) with intermediate PSA levels of 4.1 to 10.0 ng./ml. and normal or asymmetric nonindurated rectal examinations. Only 5 of 79 patients (6.3%) with a normal digital rectal examination and PSA level of less than 4.0 ng./ml. demonstrated carcinoma on biopsy. Of the 5 patients 4 had annual increases in PSA of 40% or greater. While hypoechoic sectors were more than twice as likely as isoechoic sectors of the prostate to contain malignancy on biopsy, nearly 37.6% of the cancers were found in isoechoic sectors. A strategy of performing biopsy of only hypoechoic sectors would have misdiagnosed 24.6% of the patients with prostate cancer. We conclude that serum PSA is the most accurate of the 3 diagnostic tests evaluated. We also recommend a systematic sextant biopsy technique.
We present the results of a prospective multicenter clinical trial of nearly 5,000 men in which prostate specific antigen (PSA) density was compared to the serum PSA concentration alone for early detection of prostate cancer. All men were evaluated with PSA and digital rectal examination. If PSA was elevated (greater than 4 ng./ml., Hybritech Tandem assay) or digital rectal examination was suspicious, transrectal ultrasound guided biopsies were recommended. Prostate volume was estimated by transrectal ultrasound measurements using a prolate ellipse volume calculation and PSA density was calculated by dividing serum PSA concentration by gland volume. Using a PSA density cutoff of 0.15 as recommended in the literature enhanced specificity but at the cost of missing half of the tumors. Of the organ confined neoplasms 47% were detected by a PSA of greater than 4.0 ng./ml. but they were missed by a PSA density of more than 0.15.
In hopes of limiting low-yield prostate biopsies, results of digital rectal examination (DRE), transrectal ultrasound (TRUS), prostate specific antigen (PSA) and age-related PSA values, gland-volume-adjusted PSA levels, and longitudinal PSA changes were analyzed to identify their cost-effectiveness as prognostic indicators in screening, biopsy, and follow-up of patients with prostate cancer.
Twenty-nine hundred men with complete data sets from an initial cohort of 2999 men with an annual follow-up for up to 5 years were examined. Intrapatient PSA and gland-volume variability, optimal PSA operating points (o.p.), and test performance scores were determined for each parameter. Decision analysis was then applied retrospectively to each parameter to determine the cancer detection yield, biopsy requirements, and costs for commonly used detection strategies.
For the initial screening decision, the optimal PSA o.p. was 3.0 ng/ml but increased to 5.0 ng/ml in combination with DRE, whereas age-related PSA performed no better than did PSA. The mean intrapatient variability in TRUS gland volume (+5.5 cc) relative to mean volume (34 cc) was 16%, which was less than the 28% (0.64/2.3 ng/ml) relative variability for PSA. For biopsy decisions, using PSA density (PSAD) with a level of 0.12 ng/ml/cc there was no significant difference in accuracy compared with the systematic biopsy of all patients with elevated PSA or age-related PSA levels. Rather than perform systematic biopsy on all patients with PSA levels greater than 4 ng/ml, decision analysis showed that a 16-55% reduction in biopsies could be achieved with a respective cancer loss of 4-25% by limiting biopsy to patients with an increased PSAD level and/or abnormal results of DRE. Using age-related PSA criteria in combination with DRE reduced biopsies by 12% but resulted in minimal cost reductions. The greatest biopsy reduction relative to cancer yield and lowest cost per cancer detected occurred with PSAD-driven biopsy strategies. During follow-up, longitudinal changes in absolute PSA and PSAD levels were significantly better (P < 0.05) than the percentage change in PSA levels per year.
Cost-effective prostate cancer detection with PSA as a parameter is better achieved if screening and biopsy decisions are not linked intimately. A tailored-biopsy approach for patients with disproportionately elevated PSA levels of suspicious DRE results in the greatest biopsy reduction by selecting lower risk groups for more conservative follow-up.
We quantify the causes of elevated serum prostate specific antigen (PSA) concentrations in men whose prostate biopsies repeatedly showed no cancer.
The effects of prostate volume, inflammation, echogenicity on ultrasound and calculi were examined in a large PSA-based screening population of 148 men with serum PSA concentrations greater than 4.0 ng./ml., findings suspicious for cancer on digital rectal examination and multiple negative biopsies. These men were selected and compared to 64 men with suspicious rectal examinations, multiple negative biopsies and serum PSA concentrations of 4.0 ng./ml. or less.
The high PSA group had larger prostates (68 versus 33 cc, p = 0.0001) and significantly more subclinical prostatic inflammation. Acute and chronic inflammation was more prevalent in the high PSA group (63% versus 27%, p = 0.0001 and 99% versus 77%, p = 0.0001, respectively). A simultaneous regression analysis showed that prostatic size accounted for 23%, inflammation 7%, prostatic calculi 3% and nonisoechoic ultrasound lesions 1% of the serum PSA variance.
Prostate volume and inflammation are the most important factors contributing to serum PSA elevation in men without clinically detectable prostate cancer.
To evaluate the role of ultra sound-guided systematic and lesion-directed biopsies, biopsy gleason score, preoperative serum prostate-specific antigen (PSA) as three objective and reproducible variables to provide a reliable combination in preoperative identification of risk of extraprostatic extension in patients with clinically localized prostate cancer.
The case records of 813 patients who underwent radical prostatectomy for clinically localized prostate cancer were analyzed. All had multiple systematic biopsies, two to three from each lobe, in addition to lesion-directed biopsies. Additionally, biopsies were done on seminal vesicles (SVs), if abnormal. Based on biopsy results, patients were classified as having stage B1 (T2a-T2b) or B2 (T2c) disease, depending on whether biopsies from one or both lobes were positive and stage C (T3) if there was evidence of SV involvement by biopsy of biopsies from areas of extracapsular extension as seen on transrectal ultrasound (TRUS) were positive. Logistic regression analyses with log likelihood chi-square test was used to define the correlation between individual as well as combination of preoperative variables and pathologic stage.
On final pathologic examination, 473 (58%) patients had organ-confined disease, 188 (23%) had extracapsular extension (ECE), with or without positive surgical margins, and 72 (9%) had SV involvement. Eighty (10%) patients had pelvic lymph node metastases. Biopsy-based staging was superior to clinical staging in predicting final pathologic diagnosis. Logistic regression analyses revealed that the combination of biopsy-based stage, preoperative serum PSA, and biopsy Gleason score provided the best prediction of final pathologic stage. Probability plots constructed with these data can provide significant information on risk of extraprostatic extension in individual patients.
This study demonstrates that TRUS-guided systematic biopsy in combination with preoperative serum PSA and biopsy Gleason score may provide a cost-effective approach for management decisions and prognostication in patients with prostate cancer.
This study examined the clinical significance of non-complexed (free) prostate-specific antigen (PSA) in the differential diagnosis of prostate cancer with an emphasis on patients with total PSA values between 4.0 and 10.0 ng/mL (the diagnostic gray zone).
Serum samples were obtained from three specimen banks. Patient samples consisted of 55 untreated histologically confirmed primary cancer, 62 men with untreated benign prostatic disease histologically confirmed by 6 negative sextant biopsies, and 64 asymptomatic healthy male controls with normal digital rectal examinations and PSA values less than 4.0 ng/mL. All patients were between the ages of 50 and 75 years. Total PSA levels were determined using the PA immunoassay performed on the TOSOH AIA-1200 automated immunoassay instrument. Free PSA levels were determined using a monoclonal-polyclonal antibody sandwich radioimmunoassay. The proportion of free to total PSA was calculated by dividing the patient's free PSA value by the total PSA value.
When all subjects were included, both total PSA and the proportion of free to total PSA significantly differentiated between patients with prostate cancer and patients with benign histologic conditions (P < 0.0001). However, in men with total PSA values between 4.0 and 10.0 ng/mL, the proportion of free to total PSA significantly differentiated between patients with benign and malignant histologic conditions (P = 0.0004), whereas the total PSA did not (P = 0.13). Among this subgroup of patients, the analysis of sensitivity and specificity showed that the proportion of free to total PSA had a clearly higher specificity compared with that of the total PSA at the same level of sensitivity.
Measurement of the free PSA level in a patient's serum and calculation of the proportion of free to total PSA enhances the ability to distinguish benign histologic conditions from cancer while retaining high sensitivity for detecting cancer in men who present with total PSA levels between 4.0 and 10.0 ng/mL. A large-scale population-based study is currently in progress to confirm this preliminary finding.
Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%.
Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer.
The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer.
If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer.
We evaluated the usefulness of an ultrasensitive immunoassay for prostate specific antigen (PSA), modified from the standard Yang Pros-Check PSA test and with a biological detection limit for PSA in serum of 0.07 ng./ml., to detect residual prostate cancer at an earlier date. We studied retrospectively serial frozen serum samples from 22 prostate cancer patients after radical prostatectomy who later had residual cancer with detectable PSA levels of 0.3 ng./ml. or more by the standard PSA test. As controls we studied 33 cystoprostatectomy patients (for bladder cancer) without histological evidence of prostate cancer and 23 patients after radical prostatectomy who had the highest probability of cure of the cancer. All control patients without cancer had PSA values (282 of 283 samples, 99.6%) of less than 0.1 ng./ml. This value was called the residual cancer detection limit. In the 22 patients with recurrent cancer the ultrasensitive assay detected cancer recurrence (PSA 0.1 ng./ml. or more) much earlier (median 202 and mean 310 days) than the standard assay (PSA 0.3 ng./ml. or more). On screening 187 current post-radical prostatectomy patients without evidence of cancer by the standard assay the ultrasensitive assay detected 21 (11.2%) with evidence of residual cancer, that is PSA level of 0.1 ng./ml. or more. We conclude that an ultrasensitive assay for PSA can detect residual cancer after radical prostatectomy much earlier than current immunoassays for PSA. Earlier detection of residual cancer may improve long-term survival by allowing for earlier institution of adjuvant therapy.
This study was performed to evaluate the effect of positive margins, Gleason grade, and capsular penetration on progression after radical prostatectomy.
The authors followed 507 men with totally embedded retropubic prostatectomy specimens performed for clinical Stages A and B prostate cancer for a mean of 3.9 years.
Fifty-nine percent of the specimens had negative margins, 37% had focally positive margins, and 4% had extensive positive margins. Although some positive margins were the result of extensive and/or high-grade tumor, in many cases, the tumors only focally reached the capsular margin such that positive margins resulted from an inability to remove additional soft tissue surrounding the prostate. Gleason sum 7 tumors had a significantly higher progression rate compared with Gleason sum 5 or 6 ones, although historically Gleason sum 5-7 lesions had been considered together as intermediate-grade tumors. In a multivariate analysis, positive margins and Gleason sum strongly correlated with progression, whereas capsular penetration did not. Only approximately 50% of patients with positive margins experienced disease progression during 5 years of follow-up. The most common single sites of positive margins were distal (22%), posterior (17%), and posterolateral (14%); 22% of positive margins were extensive. Only four patients (0.8% of the total) had positive margins only in the region of the spared neurovascular bundle and experienced progression.
The most likely explanation for the discrepancy between margins and progression is that some of these margins represented artifactually positive margins caused by the unique problems with handling and assessing radical prostatectomy specimens. Radical prostatectomy provided excellent local control, with only 8% of patients exhibiting local recurrence. Sixty-one percent of men with progression had an elevated serum prostate-specific antigen level as their only manifestation of progression. The significance of isolated elevated serum prostate-specific antigen levels is uncertain, and long-term morbidity and mortality will depend on whether these patients have local disease or occult distant metastases.