Thomas A. Stamey

Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate.

To compare the clinical usefulness of the serum markers prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), we measured them by radioimmunoassay in 2200 serum samples from 699 patients, 378 of whom had prostatic cancer. PSA was elevated in 122 of 127 patients with newly diagnosed, untreated prostatic cancer, including 7 of 12 patients with unsuspected early disease and all of 115 with more advanced disease. The PSA level increased with advancing clinical stage and was proportional to the estimated volume of the tumor. The PAP concentration was elevated in only 57 of the patients with cancer and correlated less closely with tumor volume. PSA was increased in 86 percent and PAP in 14 percent of the patients with benign prostatic hyperplasia. After radical prostatectomy for cancer, PSA routinely fell to undetectable levels, with a half-life of 2.2 days. If initially elevated, PAP fell to normal levels within 24 hours but always remained detectable. In six patients followed postoperatively by means of repeated measurements, PSA--but not PAP--appeared to be useful in detecting residual and early recurrence of tumor and in monitoring responses to radiation therapy. Prostate massage increased the levels of both PSA and PAP approximately 1.5 to 2 times. Needle biopsy and transurethral resection increased both considerably. We conclude that PSA is more sensitive than PAP in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy. However, since both PSA and PAP may be elevated in benign prostatic hyperplasia, neither marker is specific.

Random Systematic Versus Directed Ultrasound Guided Transrectal Core Biopsies of the Prostate

Random systematic ultrasound guided transrectal core biopsies of the prostate were compared to directed biopsies of specific hypoechoic defects in 136 men with abnormal prostates on digital rectal examination. Prostate cancer was diagnosed in 83 of 136 patients (62 per cent). In 80 of 83 individuals (94 per cent) the cancer was detected by random systematic biopsies alone. Of 57 men in whom random systematic and directed biopsies were obtained the results of biopsy agreed in 86 per cent, while in 9 per cent random systematic biopsies found cancers missed by directed biopsies and in 5 per cent directed biopsies diagnosed cancers missed by random systematic prostate biopsies. Ultrasound guided random systematic biopsy is simple and easily learned. When combined with additional directed biopsies of the rare hypoechoic areas not included in the pattern of systematic sampling, it provides a highly accurate means to diagnose prostate cancer, minimizing observer and sampling errors. This technique of prostate mapping with 6, 1.5 cm. cores provides valuable additional information on cancer volume, Gleason grade and the potential location of surgically positive margins, all without compromising the operation or the chance for a surgical cure.

Zonal distribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread

For 104 prostate glands obtained at radical prostatectomy for adenocarcinoma, we mapped the tumor outline and determined the tumor volume, grade, and location relative to the transition zone boundary and location of the central zone. Among the 88 cancers whose probable zone of origin could be identified, 68% arose in the peripheral zone, 24% arose in the transition zone, and 8% arose in the central zone. Transition zone carcinomas had usually been diagnosed by transurethral resection (TUR) and often appeared to arise within BPH nodules; only two of 67 non-transition zone carcinomas had been diagnosed at TUR. Two-thirds of 21 transition zone cancers showed a distinctive histologic appearance; they were made up of columnar clear cells lining glands of widely variable size and contour. The transition zone boundary appeared to act as a barrier to the spread of non-transition zone carcinomas. We conclude that carcinoma typically arises in the region of the prostate that is susceptible to benign prostatic hyperplasia and that the great majority of Stage A (TUR) cancers are transition zone cancers. Non-transition zone cancers detectable at TUR are predominantly large tumors that are poorly differentiated and lack the clear cell histologic pattern.

Prostate Specific Antigen in the Diagnosis and Treatment of Adenocarcinoma of the Prostate. II. Radical Prostatectomy Treated Patients

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. Prostate specific antigen is useful as a preoperative marker because no patient with lymph node metastasis had serum levels of less than 10 ng. per ml. (4 times the upper limit of normal range). Of the patients with greater than 50 ng. per ml. two-thirds had microscopic lymph node metastasis and 90 per cent had seminal vesicle invasion. Serum prostatic acid phosphatase levels showed a significantly weaker correlation with cancer volume (r equals 0.51) and every other pathological parameter. Of the patients 73 per cent had serum prostatic acid phosphatase levels in the normal range (0 to 2.1 ng. per ml.), including 7 per cent who had pelvic lymph node metastasis. Postoperative prostate specific antigen values were available in 97 of 102 patients, with a mean and maximum followup of 12 and 38 months. No patient with pelvic lymph node metastasis achieved an undetectable prostate specific antigen level without adjunctive therapy (hormonal or radiation). No difference in preoperative or postoperative prostate specific antigen levels, cancer volume, seminal vesicle invasion or incidence of pelvic lymph node metastasis was seen between patients with no capsular penetration and those with minimal capsular penetration (1 cm. or less total linear extent of full thickness penetration), providing the first quantitative evidence that small amounts of capsular penetration may not be of biological or prognostic significance.

DETERMINATION OF PROSTATE VOLUME BY TRANSRECTAL ULTRASOUND

Estimation of prostate gland volume with transrectal ultrasound may provide important information in the evaluation of benign and malignant prostatic diseases. To determine the most accurate means of volume estimation 150 patients underwent transrectal ultrasound with 15 separate methods of volume estimation. All patients underwent subsequent radical prostatectomy or cystoprostatectomy. Prostate specimen weights were compared with the results of each volume estimation method. Step-section planimetry, previously assumed to be the most accurate means of volume measurement, exhibited a Pearson correlation coefficient of 0.93. The elliptical volume, widely used as an alternative to planimetry, demonstrated a correlation coefficient of 0.90. The most accurate method to estimate prostate weight (r = 0.94) was a variation of the prolate spheroid formula, expressed as pi/6 (transverse dimension)2 (anteroposterior dimension). When different volume ranges were considered, this prolate spheroid formula provided the closest estimate of weight in glands of less than 40 gm. and those in the 40 to 80 gm. range. The most accurate method to estimate prostates weighing greater than 80 gm. was the formula pi/6 (transverse dimension)3.

Morphometric and Clinical Studies on 68 Consecutive Radical Prostatectomies

Morphometric reconstructions of 68 consecutive radical prostatectomies were analyzed for cancer volume, extent of complete capsular penetration, microscopic seminal vesicle and lymph node invasion, and histological differentiation, all of which were strongly interrelated. At less than 3.0 cc cancer volume, only 6 of 34 prostates (18 per cent) showed capsular penetration compared to 27 of 34 (79 per cent) with tumors of greater than 3.0 cc. Seminal vesicle invasion occurred once in 34 tumors of less than 3.0 cc and 15 times in those greater than 3.0 cc. All 6 patients with metastases to lymph nodes, 2 with early postoperative development of bone metastases and 4 of 5 with reappearance of detectable prostate specific antigen postoperatively had cancer volumes of greater than 4.0 cc. Correlation of digital rectal examination with cancer volume showed that of 39 palpable nodules in prostates with a cancer volume of less than 4.0 cc 30 (77 per cent) occupied 50 per cent or less of the length of 1 lobe (clinical stage B1 in our classification). Of 22 palpable lesions in tumors of greater than 4.0 cc 21 (95 per cent) exceeded 50 per cent of 1 lobe in the longitudinal extension (stage B2) or they represented bilaterally palpable disease (stage B3). Capsular penetration into the periprostatic fat occurred most commonly in the dorsolateral area of the neurovascular bundle, including 10 of 12 tumors less than 4.0 cc in volume (stage B1) and 19 of 21 with greater than 4.0 cc in tumor volume (stages B2 and B3). All 10 of the stage B1 cancers were free of contralateral lobe capsular penetration while 1 of the 13 stage B2 nodules had minimal contralateral capsule penetration in the area of the neurovascular bundle. We believe that the modified nerve-sparing radical prostatectomy should be limited to the contralateral side in stage B disease.

Histologic differentiation, cancer volume, and pelvic lymph node metastasis in adenocarcinoma of the prostate

The Gleason grading system for prostate cancer was applied quantitatively to analysis of entire tumors in 209 radical prostatectomy specimens from patients with clinical Stage A and Stage B carcinoma. Percentage of poorly differentiated tumor (Gleason histologic pattern 4 and/or 5) was related to quantitated cancer volume, cancer location within the prostate, and presence or absence of pelvic lymph node metastasis. A strong correlation was found between cancer volume, percentage of poorly differentiated cancer, and nodal metastasis. Twenty‐two of 38 patients with more than 3.2 cc of Gleason histologic pattern 4‐5 cancer had nodes with positive results, compared with one of 171 patients with less than 3.2 cc of pattern 4‐5 cancer. Gleason histologic patterns 1 and 2 cancer was found mainly in a small subgroup of tumors whose site of origin was in the anatomic transition zone and whose volume was less than 1 cc. Gleason “cribriform” histologic pattern 3 cancer was thought to represent mainly intraductal carcinoma. Its increase in area with increasing cancer volume paralleled the increase in pattern 4 cancer and was counter to the decrease in other types of pattern 3 cancer.

Interstitial cystitis early diagnosis, pathology, and treatment

In a retrospective review, 52 patients with interstitial cystitis have been studied. Patients with persistent lower tract irritative symptoms, repeatedly sterile urine, and negative urine cytology must be suspected of having interstitial cystitis, and a diagnosis of urethral syndrome in such patients is highly questionable until cystoscopy under anesthesia has been performed. We believe that the finding of multiple petechia-like hemorrhages (glomerulations) on the second distention of the bladder is the hallmark of interstitial cystitis, and that a reduced bladder capacity and a Hunners ulcer represent a different (classic) stage of this disease. In all stages, the characteristic histologic finidng is submucosal edema and vasodilation. The presence of eosinophils and mast cells is variable, and even in the classic disease the muscularis often appears to be normal. Immuno fluorescent studies and laboratory tests, including the fluorescent antinuclear antibody test (FANA), have not helped us to diagnose (or investigate) interstitial cystitis. Bladder instillations with a 0.4 per cent solution of oxychlorosene sodium (Clorpactin WCS-90) have provided remarkable relief for many patients with this disease, particulary those with the classic form.

Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume

Background. The serum marker prostate‐specific antigen (PSA) has been shown to be proportional to the volume of prostate cancer (Yang polyclonal assay). One gram of cancer on average produces 3.5 ng/ml of PSA elevation. Thus, changes in PSA in untreated patients should reflect tumor growth rate and the shape of the growth curve.

Ultrasound Guided Transrectal Core Biopsies of the Palpably Abnormal Prostate

Ultrasound imaging and ultrasound guided transrectal core biopsies were performed in 251 consecutive men with abnormal prostates on digital rectal examination. A hypoechoic defect on ultrasound was identified in 227 of 251 patients (90 per cent) corresponding to the area of palpable nodularity or abnormal firmness. A mean of 6.25 biopsies were obtained per patient using a commercially available spring-loaded gun. Biopsies were positive for cancer in 165 of the 251 prostates (66 per cent). Palpable nodules more often were hypoechoic and more often contained cancer than less distinct areas of abnormal firmness on digital examination. Among the clinical stages B1, B2 and B3 nodules 70, 76 and 88 per cent, respectively, were positive for cancer, as were 100 per cent of the clinical stage C prostates. Of 77 abnormally firm, nonnodular prostates 36 per cent were positive for cancer. Random biopsy of the contralateral normal lobe in 56 men with clinical stage B1 or B2 nodules showed cancer present contralaterally in 42 and 60 per cent, respectively; 20 per cent had positive biopsies despite a contralateral isoechoic ultrasound. In 78 patients with prior digitally guided biopsies, ultrasound guided biopsies confirmed previously diagnosed cancers in 94 per cent. However, in 23 of 43 patients (53 per cent) with previous negative digitally guided biopsies, ultrasound guided biopsies made the new diagnosis of cancer. Complications, including post-biopsy fever and bleeding, occurred in 6 of 251 patients (2.4 per cent). The combination of the new spring-loaded biopsy guns and transrectal ultrasound guidance of biopsies provides the urologist with a tool that allows multiple prostate cores to be obtained safely and painlessly, reducing the sampling error and increasing the accuracy in diagnosing prostate cancer in the man with a palpable abnormality of the prostate.