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Prostate carcinoma screening in the county of Tyrol, Austria

1997; Wiley; Volume: 80; Issue: 9 Linguagem: Inglês

10.1002/(sici)1097-0142(19971101)80

1097-0142

Andreas Reissigl, Wolfgang Horninger, K. Fink, Helmut Klocker, Georg Bartsch,

Bladder and Urothelial Cancer Treatments

CancerVolume 80, Issue 9 p. 1818-1829 CommunicationFree Access Prostate carcinoma screening in the county of Tyrol, Austria† Experience and results Andreas Reissigl M.D., Corresponding Author Andreas Reissigl M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaProfessor of Urology, Department of Urology, Anichstraße 35, 6020 Innsbruck, Austria===Search for more papers by this authorW. Horninger M.D., W. Horninger M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorK. Fink M.D., K. Fink M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorH. Klocker Ph.D., H. Klocker Ph.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorG. Bartsch M.D., G. Bartsch M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this author Andreas Reissigl M.D., Corresponding Author Andreas Reissigl M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaProfessor of Urology, Department of Urology, Anichstraße 35, 6020 Innsbruck, Austria===Search for more papers by this authorW. Horninger M.D., W. Horninger M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorK. Fink M.D., K. Fink M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorH. Klocker Ph.D., H. Klocker Ph.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this authorG. Bartsch M.D., G. Bartsch M.D. Prostate Center of the Department of Urology, University of Innsbruck, Innsbruck, AustriaSearch for more papers by this author First published: 20 November 2000 https://doi.org/10.1002/(SICI)1097-0142(19971101)80:9 3.0.CO;2-7Citations: 41 † Presented at the American Cancer Society Workshop: Review of Current Data Impacting Early Detection Guidelines for Prostate Cancer, Phoenix, Arizona, March 10-11, 1997. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract BACKGROUND This article summarizes the experience and results of different prostate carcinoma screening projects using total prostate specific antigen (PSA) as the initial test and different diagnostic tests to improve specificity. METHODS The seven projects studied included 1) a mass screening study using PSA as the initial test in 21,079 volunteers; 2) an investigation of the usefulness of normal and age-referenced PSA cutoffs in 1618 men; 3) a PSA-based screening study of 2272 asymptomatic blood donors; 4) an investigation of the incidence and clinical significance of transitional zone carcinoma in 340 men with negative rectal examination findings and clearly visible prostatic zones on three-dimensional transrectal ultrasound; 5) determination of percent free PSA in one retrospective and two prospective screening studies to define the optimal range of total PSA and determine the appropriate cutpoints for percent free PSA within this range; 6) evaluation of the diagnostic benefit of PSA transitional zone density in 308 screening volunteers; and 7) a study of the impact of PSA-based screening on the percentage of incidental prostate carcinoma diagnosed in 1543 men undergoing transurethal resection of the prostate. RESULTS 1) Of the 21,078 volunteers, 1618 (8%) had elevated PSA levels. Of these men, 778 (48%) underwent biopsies; 197 biopsies (25%) were positive for prostate carcinoma and 135 patients underwent radical prostatectomy. Ninety-five of the 135 pathologically staged lesions (70%) were found to be organ-confined. 2) A PSA cutoff of 2.5 ng/mL in men age 45-49 years and of 3.5 ng/mL in men age 50-59 years with normal digital rectal examination findings resulted in an 8% increase in both the number of biopsies (66 of 778) and the detection rate of organ-confined disease. 3) Of the 2272 men, 284 had elevated PSA levels and prostate carcinoma was detected in 62 men. All patients underwent radical prostatectomy and histologic examination revealed organ-confined disease in all but eight men. 4) Ninety-eight of 340 men (28.8%) had biopsies positive for carcinoma; 28 of these patients (28.5%) had carcinoma that originated in the transitional zone only. 5) In the retrospective study, receiver operating characteristic curve analysis showed that by using a percent free PSA of 18% as a biopsy criterion in men with an elevated PSA serum level, 37% of the negative biopsies could be eliminated although 94% of all carcinomas would still be detected. In the first prospective study, 106 of 158 men with elevated total PSA values between 2.5 and 10.0 ng/mL were further evaluated and 37 prostate carcinomas were detected. By using a percent free PSA of ≤22% as a biopsy criterion, 30% of the negative biopsies could be eliminated although 98% of the carcinomas would still be detected. In the second prospective study, 120 of 465 men with total PSA levels between 1.25 and 6.49 ng/mL, a percent free PSA of 0.22 ng/mL/cc as a biopsy criterion, 24.4% of negative biopsies could be avoided without missing the detection of a single carcinoma. 7) In the prescreening era the incidence of T1a Grade 1 and 2 carcinomas was 3.1% and the incidence of T1a Grade 3 and T1b carcinoma was 2.3%, whereas in the years after the establishment of PSA-based screening the incidence was 4.6% and 1.03%, respectively. CONCLUSIONS These data suggest that PSA-based screening increases the detection rate of clinically significant and organ-confined tumors. Percent free PSA and PSA transitional zone density provide an additional diagnostic benefit over total PSA. Cancer 1997; 80:1818-29. © 1997 American Cancer Society. Several studies have demonstrated that prostate specific antigen (PSA)-based screening is the most effective screening method; however, most of these studies were performed in men referred to urologic care settings because of signs and symptoms of the disease.1, 3 It is only recently that large scale screening studies have been conducted in asymptomatic men within a limited time frame.4 A mass screening project was performed in Tyrol, one of nine federal states of the Republic of Austria. Tyrol is an alpine region in the western part of Austria with 631,410 inhabitants (324,161 females and 307,249 males) in an area of 12,647 square kilometers. The geographic situation as well as the willingness of the general population to participate in preventive medical programs caused the authors to launch a statewide mass screening program with PSA as the initial test for the early detection of prostate carcinoma. Of the 307,249 male inhabitants, 65,000 were age 45-74 years. The authors recommended that men within this age range undergo screening, and information to this effect was distributed to all Tyrolean males by press, radio, and television. The screening project was performed in collaboration with general practitioners, medical officers, urologists, and the Tyrolean Blood Bank of the Red Cross. All coworkers were fully informed regarding the guidelines for the withdrawal, storage, and shipping of the blood samples. PSA was assessed immediately on arrival of the blood or serum samples. All volunteers and/or referring physicians were informed in writing about the results. In case of elevated PSA levels the volunteers were invited to undergo further urologic evaluation, whereas men with normal PSA levels were invited to have a repeat PSA test 1 year later. Projects 1. Results of a mass screening with PSA as the initial test. 2. Comparison of different PSA cutpoints. 3. PSA study in blood donors. 4. Incidence and significance of transitional zone carcinoma. 5. Determination of the ratio of free/total PSA in screening volunteers to define the optimal range of total PSA and determine the appropriate cutpoints for percent free PSA within this range. 6. Evaluation of the diagnostic benefit of PSA transitional zone (TZ) density. 7. PSA-based screening and percent of incidental prostate carcinoma. The Tyrol Project This mass screening project was conducted between October 1993 and September 1994 with PSA as the initial test for the early detection of prostate carcinoma. Approximately 65,000 Tyrolean males age 45-75 years were invited to participate in this screening program free of charge. Twenty-one thousand and seventy-eight male volunteers (32%) responded to press releases, radio, and TV programs asking healthy men to participate in a PSA screening test for prostate carcinoma. All volunteers underwent determination of serum PSA concentration (Abbott IMX assay; Abbott Laboratories, Chicago, IL) in the same laboratory using age-referenced PSA levels.5 Age was defined as the subject's age on the day of PSA assessment. All males who had elevated PSA concentrations according to age-referenced levels were invited to undergo further urologic evaluation including digital rectal examination and ultrasound-guided biopsies using a spring-loaded device. Digital rectal and transrectal ultrasound examinations were performed by the same four urologists. With the help of three-dimensional ultrasound equipment ultrasonography was performed in three planes (sagittal, horizontal, and coronal), and biopsies were performed under ultrasound guidance with an automatic biopsy gun and a 18-gauge needle (sextant biopsy). Of the 21,078 volunteers 1618 (8%) were found to have elevated PSA levels. The age distribution is shown in Table 1. Overall, biopsies were obtained in 778 of 1618 men (48%) with elevated PSA levels. In 197 of these men (25%) the biopsies were positive for prostate carcinoma. The overall carcinoma detection rate was 1.2%. Approximately 70% of these lesions were missed on digital rectal examination and were detected only by PSA determination. Transrectal ultrasound was normal in 65% of the prostate carcinoma patients. Of the 197 males presenting with carcinoma, 135 (69%) underwent radical prostatectomy. The results of pathologic staging and grading are summarized in Table 2. Overall, 95 of the 135 pathologically staged lesions (70%) were found to be organ-confined. Of these lesions, 90% were missed by digital rectal examination and detected only by PSA determination, and 82% were missed by transrectal ultrasound. Of the 40 patients presenting with advanced stage disease, 10 had microscopically positive margins, 9 showed invasion of the seminal vesicles, and 3 had pelvic lymph node metastases. Of the 135 pathologically staged tumors, 130 (97%) were judged to be clinically significant with regard to stage, grade, and volume. Table 1. Age Distribution and Number of Volunteers, Number of Biopsies, and Number of Tumors Age group (yrs) No. of volunteers No. of biopsies No. positive for carcinoma 45-49 2054 28 3 50-59 9541 142 28 60-69 7601 401 109 70-75 1882 207 57 Totals 21,078 778 197 Table 2. Pathologic Findings of 135 Radical Prostatectomy Specimens No. of tumors Pathol stage Median Gleason score 5 pT1 4.2 90 pT2 5.8 26 pT3 6.6 9 pT3c 7.2 5 pT4 7.0 3 N+ 7.3 Pathol: pathologic. Comparison of Different PSA Cutpoints This study was designed to investigate the usefulness of normal and age-referenced PSA cutoffs in a mass screening study for the early detection of prostate carcinoma. Previously, most screening studies used a PSA concentration of 4.0 ng/mL as the upper limit of normal, whereas some reports suggested the use of age specific PSA reference ranges.6 In this mass screening project, the authors used the age-referenced PSA levels described earlier. Furthermore, all men age 50-75 years with PSA levels between 4-6.5 ng/mL, which were considered normal according to age specific PSA reference ranges, were invited to undergo further urologic evaluation as described earlier. Of the 1618 men with elevated PSA levels, 66 presented with levels > 2.5 ng/mL but 4.0 ng/mL but 59 years only 5 (22%) carcinomas were considered to be of clinical significance. Thus, only a small number of life-threatening carcinomas were missed in this age group as a result of using age specific reference ranges. The detection rates of organ-confined carcinomas showed a significant age-related difference (P = 0.00004); in the younger age group (PSA level of 2.5-4.0 ng/mL) 16 of 16 tumors and 8 of 23 tumors in the older age group (PSA level of 4.0-6.5 ng/mL) were detected. The results obtained from 21,078 screening participants support the clinical usefulness of age specific reference ranges for serum PSA. PSA-Based Screening Study in Blood Donors Every year approximately 50,000 blood donors age 18-65 years are recruited by the regional Blood Bank at Innsbruck University Hospital. Donation of blood routinely involves a medical check-up comprised of various blood tests such as liver function tests, cholesterol, human immunodeficiency virus test, and other investigations. In 1991, PSA determination also was included and now is routinely performed in all male blood donors age 40-65 years. The study was launched on January 2, 1991 and performed over a period of 3 years. In this study, PSA was measured with an immunoradiometric assay (Tandem-R-PSA; Hybritech Inc., San Diego, CA). The volunteers were divided into two age groups. Group 1 included men age 40-49 years, whereas Group 2 comprised males age 50-65 years. PSA serum levels were determined at the study laboratory from a total of 2272 asymptomatic blood donors. Age Group 1: 40-49 years In this screening group, 44 volunteers presenting with serum PSA levels > 4 ng/mL were invited to undergo further urologic evaluation. In patients with abnormal findings on digital rectal examination, ultrasound-guided biopsies were performed to sample regions with palpable abnormalities and/or hypoechoic areas. In view of their young age patients in this group who had normal findings on digital rectal examination were not evaluated further. However, they were encouraged to return for annual PSA determination. Those who showed a 20% increase in PSA underwent systematic sector biopsy under ultrasound guidance. Forty-four men (8%) presenting with serum PSA levels > 4 ng/mL were evaluated further by digital rectal examination (compliance rate, 100%). Only 2 males (5%) who had suspicious findings on digital rectal examination underwent biopsy, the results of which were negative for carcinoma. Forty-two patients with PSA levels of >4 ng/mL and normal findings on digital rectal examination were encouraged to return annually for PSA assessment. Twelve showed a 20% increase in the concentration of PSA 1 year later. Among those patients biopsied, prostate carcinoma was detected in 4 (33%). Two patients who had negative biopsies in the first year presented with an increase in PSA in the second year (4.1 to 6.2 ng/mL and 4.8 to 5.8 ng/mL, respectively) and exhibited carcinoma when biopsied again. Clinical staging in the four patients presenting with carcinoma revealed nonpalpable clinically classified T2 disease in 2 men; their Gleason scores ranged from 4-8 (mean, 5.2). Radical prostatectomy was performed in all six men. Table 4 provides information on the pathologic stages. Five of the carcinomas detected were organ-confined. Only one patient had advanced disease with microscopically positive margins. None of the lesions was a possibly latent tumor. Table 4. Pathologic Stage and Grade of Carcinoma in 6 Patients (Group 1) Staging Grade (Gleason score) Advanced 4 6 7 8 pT2a pT2b pT2c pT3a 1 1 3 1 1 3 1 1 Age Group 2 (50-65 years) In this age group PSA determination was performed in a total of 1704 males. Men with serum PSA levels > 4 ng/mL were referred for transrectal ultrasonography and, depending on the findings, random or ultrasound-guided biopsies of suspicious areas. Two hundred forty of the 1704 males (14%) were found to have serum PSA levels of >4 ng/mL; only 9% of these men had suspicious findings on digital rectal examination. Biopsy specimens were obtained from all males presenting with elevated PSA levels (compliance rate, 100%). In 58 men (24%) the biopsies were positive for prostate carcinoma. The overall carcinoma detection rate was 3.4%. Forty-two of these lesions (72%) were missed on digital rectal examination and detected solely by PSA. When used to confirm suspicious findings on digital rectal examination or PSA assessment, transrectal ultrasonography yielded false-negative results in 48% of patients. In all 58 patients whose biopsy specimens had yielded prostatic lesions, clinical staging revealed nonpalpable or clinically classified T2 tumors, with Gleason scores ranging from 4-9 (mean, 5.5). All 58 patients underwent radical prostatectomy. Table 5 shows the pathologic stages. Overall, 50 of the 58 pathologically staged lesions (86.2%) were found to be organ-confined. Of the eight patients presenting with advanced carcinoma seven had microscopically positive margins, whereas only one showed invasion of the seminal vesicle; none had pelvic lymph node metastases. Only 2 tumors were microscopically focal and well differentiated and hence possibly clinically insignificant (4%). Table 5. Pathologic Stage and Grade of Carcinoma in 58 Patients (Group 2) Staging Grade (Gleason score) Organ-confined Advanced 4 5 6 7 8 9 pT1a pT1b pT2a pT2b pT2c pT3a pT3b pT3c 2 5 24 21 5 1 1 1 22 18 8 3 4 1 Using PSA-based screening a significantly higher percentage of organ-confined carcinomas could be detected (50 of 50; 100%) than by digital rectal examination (6 of 50; 12%). Of the organ-confined carcinomas 44 (88%) were missed by digital rectal examination and detected solely by PSA (Table 6). The higher the PSA level, the less likely the chance the lesion was organ-confined. Table 6. Detection of Organ-Confined Carcinoma (n = 50; Group 2) Results category Pathologic stage Digital rectal examination PSA (ng/mL) pT1a pT1b pT2a pT2b pT2c Neg 4.1-9.9 1 1 13 12 8 Neg ≥10.0 0 0 2 2 5 Pos 4.1-9.9 0 0 1 1 2 Pos ≥10.0 or more 0 0 1 0 1 PSA: prostate specific antigen; Neg: negative; Pos: positive. Incidence and Clinical Significance of TZ Carcinoma Approximately 20% of prostate carcinomas originate from the TZ.7 Although transrectal ultrasound-guided biopsies in men with elevated PSA levels and negative digital rectal examination findings have improved the diagnosis of peripheral zone carcinoma, the yield of carcinoma can be improved further by additional biopsies obtained from the TZ. To evaluate the incidence and clinical significance of TZ carcinomas two TZ biopsies were added to the routinely performed sextant biopsies in males with elevated PSA levels and negative findings on digital rectal examination. The study included 340 volunteers with negative digital rectal examination findings and clearly visible prostatic zones on three-dimensional transrectal ultrasound, who were recruited from the PSA screening program. Ultrasonography was performed in three planes (sagittal, horizontal, and coronal). The three sections of the prostate in the horizontal, sagittal, and coronal planes are displayed simultaneously on the monitor of the system. Depending on the level of the horizontal section, the relative proportions of the TZ and peripheral zone vary considerably. Cranially, the enlarged TZ dominates the horizontal plane, whereas the slightly hypoechoic peripheral zone forms a narrow band of tissue dorsal and lateral to the TZ. Caudal to the verumontanum only the peripheral zone is observed. In the coronal plane the enlarged TZ and the hypoechoic central zone, which is displaced dorsally and cranially, can be demonstrated most clearly, and the regions of the apex of the prostate and the bladder neck can be visualized even better. This plane allows for better assessment of the topographic relationships not only between the prostatic zones but also between the prostate and its surrounding structures, thus facilitating precise delineation of the prostatic zones. The additional information provided by the coronal plane permits identification of the different prostatic zones in any section. The ultrasound images were evaluated for abnormalities in the TZ before biopsies were made as described earlier. After systematic sextant biopsy, all patients underwent two additional biopsies of the TZ. These biopsies were obtained from both the right and the left portion of the TZ. The study group included 340 males. In 98 (29%) the biopsies were positive for prostate carcinoma. Of these 98 patients, 66 (67%) presented with peripheral carcinomas, which were detected by traditional sextant biopsies. Twenty-eight carcinomas (29%) originating from the TZ could only be detected by two additional TZ biopsies; 5 males (5%) presented with lesions that were located in the TZ and the peripheral zone. None of the patients showed palpable abnormalities on digital rectal examination. Eighteen men showed TZ abnormalities on ultrasound imaging; in 4 the biopsies were positive for TZ carcinoma. TZ abnormalities included hypoechoic areas and localized asymmetry at the junction of the prostatic capsule with the anterior fibromuscular stroma. Eighteen patients with proven TZ carcinoma had preoperative serum PSA levels ranging between 2.6-9.9 ng/mL (mean, 5.6 ng/mL), whereas 10 patients presented with levels > 10 ng/mL (mean, 12.2 ng/mL). Of 33 patients undergoing radical prostatectomy, 28 presented with carcinoma arising solely from the TZ, whereas 5 had carcinomas originating from the peripheral zone as well as the TZ. The pathologic stages and grades as well as the PSA levels are shown in Tables 7 and 8. Of the prostate carcinomas detected 27 of 28 cases (96%) had malignant potential, whereas only 1 tumor (4%) was microscopically focal and well differentiated and therefore possibly insignificant with regard to stage and grade. In the radical prostatectomy specimens the mean Gleason score was 7.2 (range, 4-8) for TZ carcinomas and 7.4 (range, 6-9) for carcinomas originating from the TZ as well as the peripheral zone. Overall, 71% of the pathologically staged carcinomas (20 of 28) were found to be organ-confined. All five combined TZ and peripheral zone carcinomas were advanced lesions showing invasion of the seminal vesicles in all men and, in addition, invasion of the pelvic lymph nodes in one patient. Altogether, 30% of the carcinomas detected were so-called TZ carcinomas, which corresponds to a 95% confidence interval (20-40%). Table 7. Pathologic Findings and PSA Levels of TZ Carcinomas Patients (n = 28) Pathol stage Gleason score PSA = 2.5-9.9 ng/mL PSA ≥ 10 ng/mL 1 pT1b 5 1 0 9 pT2a 4.7 7 2 10 pT2b 5 8 2 4 pT3a 5.5 2 2 4 pT3b 7 0 4 PSA: prostate specific antigen; TZ: transitional zone; Pathol: pathologic. Table 8. Pathologic Findings and PSA Levels of Carcinomas Originating in the Transition and Peripheral Zones Patients (n = 5) Pathol stage Median Gleason score PSA (ng/mL) 4 pT3c N0 7 8.5 (median) 1 pT3c N1 9 50 PSA: prostate specific antigen; Pathol: pathologic. These data support the assumption that a significant subset of prostate carcinomas originate from the TZ. Evaluation of the Clinical Utility of the Free/Total PSA Ratio in Distinguishing Benign Prostatic Disease from Prostate Carcinoma in a Screening Population Retrospective Study This study was conducted with 266 screening volunteers who were identified as having elevated serum PSA levels by means of a conventional PSA determination kit (Abbott MEIA performed on an IMX equipment). Subsequently, their diagnosis was confirmed by biopsies. The serum samples of these 266 patients were stored at -80 °C for further measurement. Free and total PSA levels were determined with the DELFIA PSA dual labeled free/total PSA kit (Wallac Oy, Turku, Finland). The mean age of the 266 men enrolled in this study was 63 years (range, 45-75 years). In 64 men (24%) the biopsies were positive for prostate carcinoma, while 202 men were histologically free of disease. Only 8 of the 64 patients with biopsy proven disease had suspicious findings on digital rectal examination. In 56 patients clinical staging revealed nonpalpable or clinical T1c carcinoma. Radical prostatectomy was performed in 48 patients. Table 9 demonstrates the pathologic stages. Overall, 33 of the 48 pathologically staged lesions were found to be organ-confined (69%). Of the 15 patients presenting with advanced disease, 2 showed invasion of the seminal vesicles and 1 had pelvic lymph node metastases. The 64 carcinoma patients had a mean total PSA of 16.4 ng/mL (range, 4.1-168.0 ng/mL), whereas the 202 patients who were histologically free of disease had a mean total PSA of 7.5 ng/mL (range, 2.6-28.2 ng/mL). The mean free/total PSA in the 64 patients with prostate carcinoma was 0.10 ng/mL. This differed significantly (P = 0.001) from the mean free/total PSA of the 202 men with negative biopsy results, which was 0.17 ng/mL (Figs. 1 (6K) and 2 (8K)). Figure 1Open in figure viewerPowerPoint Free/total prostate specific antigen (PSA) ratio in 64 patients with prostate carcinoma (Ca) and 202 patients with nonmalignant disease (non-Ca). Figure 2Open in figure viewerPowerPoint Semilogarithmic plot of free/total prostate specific antigen (PSA) ratio versus total PSA in men with prostate carcinoma and in men with nonmalignant disease. The cutoff for free/total PSA ratio (0.18) is indicated. Table 9. Pathologic Stages of 48 Radical Prostatectomy Specimens Stage No. of patients pT1b 1 pT2a 5 pT2b 10 pT2c 17 pT3a 9 pT3b 4 pT3c 2 N+ 1 To clearly distinguish benign prostatic hyperplasia (BPH) patients from prostate carcinoma patients, the authors chose a cutoff for the percentage of free/total PSA that would include virtually all prostate carcinoma patients with elevated total PSA, regardless of their digital rectal examination findings. Receiver operating characteristic (ROC) curve analysis showed that by using a free/total PSA of 18%. All four pati