Joseph E. Oesterling

Prostate Specific Antigen: A Critical Assessment of the Most Useful Tumor Marker for Adenocarcinoma of the Prostate

PSA is a kallikrein-like, serine protease that is produced exclusively by the epithelial cells of all types of prostatic tissue, benign and malignant. Physiologically, it is present in the seminal fluid at high concentration and functions to cleave the high molecular weight protein responsible for the seminal coagulum into smaller polypeptides. This action results in liquefaction of the coagulum. PSA is also present in the serum and can be measured reliably by either a monoclonal immunoradiometric assay or a polyclonal radioimmunoassay. The calculated half-life of serum PSA ranges from 2.2 to 3.2 days and the metabolic clearance rate of this tumor marker follows first-order kinetics. Digital rectal examination, cystoscopic examination and prostate biopsy all can cause spurious elevations of the serum PSA concentration. Conditions such as bacterial prostatitis and acute urinary retention also can falsely elevate the serum PSA level. Because approximately 25% of the patients with BPH only will have an elevated serum PSA concentration and BPH tissue contributes to this PSA value in a variable manner from patient to patient, it is unlikely that PSA by itself will become an effective screening tool for the early diagnosis of prostate cancer. However, if combined with digital rectal examination and/or transrectal ultrasound it may become a vital part of any early detection program. Prostatic intraepithelial neoplasia also may be associated with moderately elevated serum PSA levels. Although there is a direct correlation between the serum PSA concentration and clinical stage, PSA is not sufficiently reliable to determine the clinical stage on an individual basis. This finding also applies to pathological stage. As a result, the preoperative serum PSA concentration cannot be used to decide whether to recommend radical prostatectomy for potential cure. Low preoperative serum PSA concentrations in patients with previously untreated prostate cancers are predictive of a negative bone scan. Thus, in these select patients a staging bone scintigram may not be necessary. With respect to monitoring patients after definitive therapy, PSA is an exquisitely sensitive tumor marker. Irrespective of the treatment modality (radical prostatectomy, radiation therapy or antiandrogen treatment), PSA reflects accurately the tumor status of the patient and is prognostic of eventual outcome; this tumor marker is capable of predicting tumor recurrence months before its detection by any other method. PSA is also a most useful immunocytochemical marker. Its sensitivity and specificity to identify tissue of prostatic origin approach 100%. When compared to PAP, PSA is a more precise and meaningful marker in all clinical situations.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.

To provide information about long-term outcome after radical prostatectomy for clinically localized prostatic cancer (stage T2c or lower), we undertook a retrospective analysis of 3,170 consecutive patients (mean age 65.3 +/- 6.4 years, range 31 to 81) with a mean followup of 5 years. Complication rates for patients who underwent prostatectomy before 1988 were compared with those who underwent radical prostatectomy more recently. Of the patients 49 (1.5%), 178 (5.6%), 897 (28%) and 2,047 (65%) had clinical stages T1a, T1b, T2a and T2b,c disease, respectively. The Gleason score was 3 or less in 292 patients (9%) and 7 or greater in 782 (25%). Overall, 438 patients (14%) died, 159 (5%) of cancer. The crude 10 and 15-year survival rates for all patients were 75% and 60%, respectively, which is comparable to the expected survival of a control group (67% and 46%). The cause specific survival rates were 90% and 82%, respectively, metastasis-free survival rates 82% and 76%, local recurrence-free survival rates 83% and 75%, overall recurrence-free rates 72% and 61%, and overall recurrence plus prostate specific antigen progression-free (greater than 0.2 ng./ml.) rates 52% and 40%, respectively. Clinical stage did not significantly affect survival but tumor grade was associated: 10 and 15-year cause specific survival rates were 95% and 93%, respectively, for a Gleason score of 3 or less, 90% and 82%, respectively, for a score of 4 to 6, and 82% and 71%, respectively, for a score of 7 or more. Of all patients 26% received adjuvant treatment (hormonal and/or radiation) within 3 months postoperatively because of advanced local pathological stage (pT3 or higher) or margin positive disease. The 30-day mortality rate was 0.3% (0% for 1,728 patients who underwent surgery in 1988 or later). Only 1 patient in the 70 year or older age group died during hospitalization. Complications decreased with time. In a contemporary group the complications were rectal injury in 0.6% of the patients, colostomy in 0.06%, myocardial infarction in 0.4%, deep venous thrombosis in 1.1%, pulmonary embolism in 0.7% and total urinary incontinence (3 or more pads per day) in 0.8%. Recent intraoperative blood loss was a median of 600 ml., and the incidence of recent need for any transfusion was 31% and it is presently less than 5%. In this series patients undergoing radical prostatectomy for clinically localized prostate cancer were usually healthy and, thus, had low co-morbidity. Survival rates at 10 and 15 years compare favorably with those of an age-matched control group.(ABSTRACT TRUNCATED AT 400 WORDS)

The prevalence of Prostatism: A Population-Based Survey of Urinary Symptoms

To establish the age-specific prevalence of urinary symptoms among a community-based cohort of men, a randomly selected sample of men were screened and invited to participate in a longitudinal survey of urinary symptoms. The population of Olmsted County, Minnesota, as enumerated by the Rochester Epidemiology Project, formed the sampling base for this study. Men between 40 and 79 years old with no history of prostate or other urological surgery, and who also were free of conditions associated with neurogenic bladder were invited to participate. A previously validated questionnaire was completed by the subject. Urine flow measures, current medications and family histories of urinary disease were also obtained. Nonresponse corrected scores for a composite of obstructive symptoms showed moderate to severe symptomatology among 13% of the men 40 to 49 years old and 28% of those older than 70 years. Prostatism is a highly prevalent symptom complex among unselected men in the community. The specific urinary symptoms of nocturia, weak stream, restarting, urgency and sensation of incomplete emptying are strongly age-related and, therefore, may be predictive of a prostatic disease process.

PROSTATE SPECIFIC ANTIGEN: A DECADE OF DISCOVERY-WHAT WE HAVE LEARNED AND WHERE WE ARE GOING

PURPOSE Many advances have occurred during the last decade in the clinical use of prostate specific antigen (PSA) for detecting, staging and monitoring prostate cancer. We review the clinical usefulness and limitations of serum PSA as a tumor marker of prostate cancer. MATERIALS AND METHODS The English language literature was reviewed with respect to the major contributions and limitations of PSA in present clinical practice. RESULTS Although controversial, age specific PSA reference ranges can improve the sensitivity for prostate cancer detection in young men and the specificity in older men. Percent free PSA improves the specificity for prostate cancer detection in men with PSA values between 4 and 10 ng./ml., and a PSA density of greater than 0.15 may better distinguish benign prostatic hyperplasia from prostate cancer. PSA velocity can improve the ability to detect prostate cancer when 3 serial PSA values are measured during a 2-year period. For prostate cancer staging PSA is most useful combined with clinical stage and Gleason score in multivariate analysis. Percent free PSA may prove useful for staging prostate cancer but further clinical trials are needed to determine its clinical usefulness. PSA is the most clinically useful means to monitor disease recurrence after treatment of prostate cancer. With ultrasensitive PSA assays it is now possible to increase the lead time for detection of disease recurrence by several months. CONCLUSIONS During the last decade much of the focus has been on improving the ability of this tumor marker to detect prostate cancer. PSA remains the best and most widely used tumor marker in urology today.

Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia.

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. Consequently, serum prostate specific antigen levels do not reflect tumor burden and pathological stage accurately in individual patients for 2 reasons: 1) the unpredictable contribution from the benign prostatic hyperplasia component of the gland and 2) the decreasing production of prostate specific antigen by higher grade lesions as tumor volume increases.

Prostate Specific Antigen in the Preoperative and Postoperative Evaluation of Localized Prostatic Cancer Treated with Radical Prostatectomy

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. With a log-linear regression model, the half-life of prostate specific antigen was calculated to be 3.15 +/- 0.09 days. From the equation PSA (t) equals PSA (2) e[-0.2197(t-2)], prostate specific antigen can be used to detect residual cancer on day t in the immediate postoperative period. With respect to long-term followup, 127 patients have been monitored for longer than 2 months postoperatively with prostate specific antigen (mean followup 2 years, range 2 months to 8.6 years). Of the 101 patients who had favorable pathological findings at operation (organ-confined cancer or capsular penetration only) 92 (91 per cent) had a followup antigen concentration in the female range (0.0 to 0.2 ng. per ml.), whereas only 5 of 26 men (19 per cent) with either seminal vesicle involvement or lymph node involvement had an antigen value that was less than 0.2 ng. per ml. All patients with a documented clinical recurrence (8 of 127, 6 per cent) had an elevated followup serum prostate specific antigen concentration. These findings suggest that preoperative levels of prostate specific antigen are not sufficiently reliable to predict final pathological stage on an individual basis in patients with early prostatic cancer, and that the antigen is a sensitive tumor marker for the detection of residual disease after radical prostatectomy and subsequent recurrence of tumor on long-term followup.

Megestrol acetate for the prevention of hot flashes.

Background Vasomotor hot flashes are a common symptom in women during menopause and in men who have undergone androgen-deprivation therapy for prostate cancer. Although treatment with estrogens in women and androgens in men can attenuate these symptoms, these hormones may be contraindicated in women with breast cancer and in men with prostate cancer. Pilot trials have suggested that the progestational agent megestrol acetate can ameliorate hot flashes in both groups of patients. Methods The patients included 97 women with a history of breast cancer and 66 men with prostate cancer who had undergone androgen-deprivation therapy. All patients had experienced bothersome hot flashes (median number per day at base line, 6.1 for the women and 8.4 for the men). After a one-week pretreatment observation period, the patients received megestrol acetate (20 mg twice daily) for four weeks, followed by placebo for four weeks, or vice versa in a double-blind manner as determined by pretreatment randomization. The patien...

The Management of Renal Angiomyolipoma

Revue des cas de la litterature mondiale et de 13 cas personnels. Un schema therapeutique systematique est propose base a la fois sur la taille de la tumeur et les symptomes

The Clinical Usefulness of Prostate Specific Antigen: Update 1994

In conclusion, PSA is the first prostate specific serum marker of clinical usefulness in urology. It represents a valuable clinical tool that has improved our ability to detect early prostate cancer and to monitor response to therapy. While large PSA screening studies have demonstrated an appreciable increase in the detection of organ confined, potentially curable prostate cancers, no study to date has yet demonstrated that the increased detection rate will decrease the prostate cancer-specific mortality rate. Yet more importantly, no study to date has demonstrated that early diagnosis using PSA will not decrease the prostate cancer specific mortality rate and until such data exist, PSA should be used to aid in early diagnosis and treatment planning for men with prostate cancer. PSA, when combined with other variables such as Gleason score and clinical stage, improves the prediction of pathological stage for prostate cancer. The introduction of PSA velocity and age specific reference ranges should further enhance the clinical usefulness of PSA. New advances in PSA research hold great promise for further improvements in PSA, and truly make it the most important and useful tumor marker for adenocarcinoma of the prostate.

Free, Complexed and Total Serum Prostate Specific Antigen: The Establishment of Appropriate Reference Ranges for their Concentrations and Ratios

PURPOSE Prostate specific antigen (PSA) exists in the serum in several molecular forms that can be measured by immunodetectable assays: free PSA, PSA complexed to alpha 1-antichymotrypsin (complexed PSA) and total PSA, which represents the sum of the free and complexed forms. We determined the normal distribution of values and established the appropriate reference ranges for these 3 molecular forms of PSA and their ratios (free-to-total, complexed-to-total and free-to-complexed PSA). Knowing the amount and ratio of these molecular forms appears to be useful in enhancing the ability of PSA to distinguish potentially curable prostate cancer from benign prostatic hyperplasia and in decreasing the number of unnecessary prostate biopsies. MATERIALS AND METHODS A total of 422 healthy men 40 to 79 years old was randomly chosen from the male population of Olmsted County, Minnesota and underwent a detailed clinical examination that included digital rectal examination, serum PSA determination and transrectal ultrasound to exclude the presence of prostate cancer. Using newly developed, monoclonal-monoclonal immunofluorometric assays for each molecular form, the free, complexed and total PSA, and the ratios of these 3 forms were determined for each study participant. RESULTS All 3 molecular forms correlated directly with patient age (r = 0.45, r = 0.43 and r = 0.45, respectively). Using the 95th percentile, the recommended age-specific reference ranges for the free, complexed and total PSA forms, respectively, are 0.5, 1.0 and 2.0 ng./ml. for men 40 to 49 years old; 0.7, 1.5 and 3.0 ng./ml. for men 50 to 59 years old; 1.0, 2.0 and 4.0 ng./ml. for men 60 to 69 years old, and 1.2, 3.0 and 5.5 ng./ml. for men 70 to 79 years old. With regard to each of the ratios (free-to-total, complexed-to-total and free-to-complexed PSA) none correlated with patient age. As a result, the appropriate upper limit of normal (95th percentile) for all 3 ratios is constant for men of all ages. These reference ranges are greater than 0.15 for free-to-total PSA ratio, less than 0.70 for complexed-to-total PSA ratio and greater than 0.25 for free-to-complexed PSA ratio. The free-to-total PSA ratio will have its greatest value for men with a serum PSA value between 2 and 10 ng./ml. CONCLUSIONS The establishment of appropriate reference ranges for free, complexed and total PSA as well as the ratios will allow the practicing urologist to incorporate these new parameters into the diagnostic evaluation of men at risk for early, potentially curable prostate cancer.