David W. Keetch

Serial Prostatic Biopsies in Men with Persistently Elevated Serum Prostate Specific Antigen Values

The objective of this study was to determine the need for repeat prostatic biopsies in men whose initial biopsy results revealed no evidence of cancer or atypia. We evaluated 1,136 men who underwent 1 or more prostatic biopsies in a longitudinal prostate specific antigen (PSA) based prostate cancer screening study that called for biopsy if the serum PSA level was greater than 4.0 ng./ml. (Hybritech assay) and findings on rectal examination or ultrasonography were abnormal or suspicious for cancer. Of the 1,136 men who underwent prostatic biopsy 391 (34%) had prostate cancer on the initial biopsy. Of 427 men who had negative initial biopsy results, a persistent serum PSA level of greater than 4.0 ng./ml. and abnormal rectal or ultrasound examination findings 82 (19%) had cancer on biopsy 2. Of 203 men with persistent abnormalities 16 (8%) had cancer on biopsy 3 and 6 of 91 (7%) had cancer on biopsy 4 or later. Thus, 96% of the cancers were detected through either biopsy 1 or 2. The median initial PSA level, followup PSA levels and the yearly rate of change in PSA were significantly greater in men whose cancer was detected compared with those of men whose cancer was not detected (6.4 versus 5.4 ng./ml., 7.4 versus 6.6 ng./ml. and 1.1 versus 0.7 ng./ml. per year, respectively). There was a trend for a higher percentage of tumors detected through serial screening to be pathologically organ confined with those detected through initial screening (73% versus 62%, p = 0.07). We conclude that men with a persistently elevated serum PSA value after an initial negative prostatic biopsy should routinely undergo at least 1 repeat biopsy to exclude adequately the presence of detectable prostate cancer.

Prospective characterization of pathological features of Prostatic Carcinomas Detected Via Serum Prostate Specific Antigen Based Screening

PURPOSE Many small (less than 0.5 cc), well differentiated, organ-confined prostate carcinomas remain clinically undetected during the life of the patient and are identified only at postmortem examination. Thus, these cancers are often called latent or autopsy cancers. There is concern that serum prostate specific antigen (PSA) based screening may preferentially detect these cancers. There are limited prospective data concerning the pathological features of carcinomas of the prostate detected in a screening program. We determined if prostatic carcinomas detected via PSA based screening resembled autopsy cancers. MATERIALS AND METHODS We assessed the pathological features of carcinomas in 100 consecutive, completely embedded radical prostatectomy specimens from men whose cancer was detected in a PSA based screening program. The tumors were evaluated for pathological stage, surgical margin status, Gleason histological grade and intraglandular tumor extent (morphometrically quantified as percentage carcinoma and tumor volume). RESULTS Of 100 carcinomas 68 (68%) were larger than 0.5 cc in volume (mean 1.7, range 0.1 to 10.7). Mean amount of carcinoma in the surgical specimen was 10.3% (range 0.1 to 41.6). Of the 100 carcinomas 94 had a Gleason score of 5 to 8 (mean 5.7) and only 6 (6%) were well differentiated (Gleason score of 4 or less). Locally advanced disease was noted in 41 cases (41%) as judged by the presence of extracapsular carcinoma and/or cancerous surgical margins. CONCLUSIONS We concluded that the pathological features of most prostatic carcinomas detected via PSA based screening do not resemble those of autopsy cancers, and that most prostatic cancers detected in screening programs are likely to be clinically important.

Optimal Therapy for the Distal Ureteral Stone: Extracorporeal Shock Wave Lithotripsy Versus Ureteroscopy

Extracorporeal shock wave lithotripsy (ESWL not equal to) is the optimal therapy for renal calculi less than 2 cm. in diameter and for proximal ureteral calculi. Controversy continues over the initial approach to distal ureteral calculi (that is below the bony pelvis): in situ ESWL versus ureteroscopy. Since February 1990, 76 distal ureteral calculi were treated at our institution using either in situ ESWL (Dornier HM3 ESWL with a Stryker frame modification in 27 patients or Siemens Lithostar electromagnetic ESWL in 22) or ureteroscopy (27 patients). Patient age and stone size were similar among the groups. All ESWL treatments were performed with the patient under intravenous sedation and on an outpatient basis. Stone-free rates were 96% for the HM3 device, 84% for the Lithostar and 100% for ureteroscopy. Retreatment was required in 3 Lithostar cases (14%) and 1 HM3 case (4%). When compared to ESWL ureteroscopy for distal ureteral stones was more time-consuming, entailed routine placement of a ureteral stent, often required general anesthesia, more often led to hospitalization and doubled the convalescence period. From a cost standpoint, ESWL on an HM3 unit was a few hundred dollars more expensive than ureteroscopy. In summary, we believe that in situ ESWL provides optimal first line therapy for distal ureteral calculi, while ureteroscopy is better reserved as a salvage procedure should ESWL fail.

Repeat Biopsy Strategy in Men with Isolated Prostatic Intraepithelial Neoplasia on Prostate Needle Biopsy

PURPOSE Isolated high grade prostatic intraepithelial neoplasia on needle biopsy of the prostate is a strong predictor of malignancy on repeat biopsy. However, the optimal repeat biopsy technique for these patients has not been defined. MATERIALS AND METHODS We reviewed the records of 66 men in whom isolated prostatic intraepithelial neoplasia was found on needle biopsy of the prostate. We evaluated the side and/or quadrant and grade of prostatic intraepithelial neoplasia on initial biopsy, and compared the findings to the location of cancer on repeat biopsy. RESULTS Of 66 men 31 (47%) had cancer on repeat biopsy, with disease on the same side of the prostate as prostatic intraepithelial neoplasia in 20 (64%). The quadrant locations of prostatic intraepithelial neoplasia and cancer matched in 6 of 12 cases (50%). Low and high grade prostatic intraepithelial neoplasia predicted the side of cancer on repeat biopsy in 3 of 5 (60%) and 17 of 26 (65%) cases, respectively. CONCLUSIONS Directing repeat biopsy solely to the side with prostatic intraepithelial neoplasia will miss cancer in approximately 35% of cases. The optimal repeat biopsy technique for patients with high grade prostatic intraepithelial neoplasia should include systematic biopsy of the prostate.

Prostatic transition zone biopsies in men with previous negative biopsies and persistently elevated serum prostate specific antigen values.

PURPOSE In men with persistently elevated serum prostate specific antigen (PSA) concentrations and prostatic biopsies that show no cancer an important question is whether the PSA elevation is caused by undetected cancer in the transition zone of the prostate gland. MATERIALS AND METHODS To evaluate this issue further we examined 166 men age 50 years of older who participated in a PSA based screening trial for prostate cancer. All men had an initially elevated serum PSA concentration of 4.1 ng./ml. or greater. They had undergone 1 or 2 sets of negative peripheral zone biopsies of the prostate but elevated serum PSA concentrations persisted. They underwent repeat biopsy of the peripheral zone as well as 2 core biopsies from the right and 2 from the left transition zone region of the prostate. RESULTS Peripheral and transition zone biopsies revealed cancer in 3 of 19 cases (16%). Cancer was present in the peripheral zone only biopsy in 14 of 19 cases (74%). Two of 19 cancers (10%) were detected only in the transition zone. Overall 17 of the 19 cancers (89%) were detected by peripheral zone biopsy. CONCLUSIONS Transition zone biopsy detects few additional prostate cancers in men with persistent serum PSA elevations and previous negative biopsies.

Morphometric Analysis and Clinical Followup of Isolated Prostatic Intraepithelial Neoplasia in Needle Biopsy of the Prostate

PURPOSE We evaluate the significance of grade and extent of isolated prostatic intraepithelial neoplasia in prostate needle biopsies as a predictor of cancer on repeat biopsy. MATERIALS AND METHODS We reviewed our experience with 58 men 50 years or older who had isolated prostatic intraepithelial neoplasia on initial prostate needle biopsy during a prostate specific antigen (PSA) based screening trial for prostate cancer. All 58 men underwent repeat biopsy to follow the initial findings of prostatic intraepithelial neoplasia. We assessed the relationship of patient age, digital rectal examination, serum PSA concentration, PSA density, prostatic intraepithelial neoplasia grade, number of foci of neoplasia and linear extent of prostatic intraepithelial neoplasia in the initial biopsy specimen to the finding of cancer on the repeat biopsy. We also compared the cancer detection rate in the 58 men with and 427 without prostatic intraepithelial neoplasia in the same screening trial. RESULTS Of 21 men with low grade and 37 with high grade prostatic intraepithelial neoplasia 4 (19%) and 19 (51%), respectively, had cancer on repeat biopsy (p < 0.02), compared to 82 of 427 (19%) without cancer or prostatic intraepithelial neoplasia on the initial biopsy. High grade prostatic intraepithelial neoplasia was a significant predictor of malignancy on repeat biopsy (p < 0.05). The number of foci of neoplasia and the linear extent of prostatic intraepithelial neoplasia on initial biopsy were not predictive of cancer on repeat biopsy. CONCLUSIONS Our results demonstrate that the presence of high grade prostatic intraepithelial neoplasia is a strong predictor of prostate cancer in men with elevated serum PSA concentrations and they should be followed with repeat biopsy.

PROSTATE-SPECIFIC ANTIGEN AS A SCREENING TEST FOR PROSTATE CANCER: The United States Experience

Serum PSA-based early detection for prostate cancer has been studied fairly extensively for the past several years. It appears that we can state fairly categorically what the relative performances of total serum PSA, DRE, and TRUS are in detecting early-stage prostate cancer; that initial screening is effective in detecting histologically significant and pathologically organ-confined prostate cancer; that annual, serial, repetitive screening, at least over a 4- to 5-year horizon, does not overdetect prostate cancer, and that the results of early detection will improve as our ability to use certain PSA transformations such as PSA density, PSA slope, age-specific PSA adjustment, and knowledge of free versus total serum PSA is better characterized. These advances in our ability to diagnose early-stage prostate cancer likely will be coupled with an increased ability to predict the behavior, curability, and significance of individual tumors. It is hoped that information soon will be available to allow physicians to categorize an individual tumor as insignificant, significant and surgically curable, or significant and incurable by standard approaches. This ability, coupled with the demonstrated ability to detect prostate cancer, will make an even more compelling argument for widespread PSA-based screening. At present, annual DRE and total serum PSA measurements are recommended for men older than 50 and among younger men at high risk for prostate cancer. All suspicious DRE findings should be evaluated with prostatic biopsy. Among younger men, PSA levels over 2.5 ng/mL should be considered worrisome and further evaluated. For men older than 65, serum PSA levels above 4 ng/mL should be considered abnormal and warrant biopsy. Men with persistent serum PSA elevation and a negative biopsy should undergo repeat biopsy at least once, and perhaps more often if PSA slope exceeds 0.75 per year, if density is greater than 0.10, or if f-PSA is less than 20%.

Familial Aspects of Prostate Cancer: A Case Control Study

PURPOSE We evaluated the importance of positive family history, age at diagnosis and history of vasectomy in predicting the risk for prostate cancer in the brothers of prostate cancer patients. MATERIALS AND METHODS A total of 1,084 men with newly diagnosed prostate cancer responded by interview to a family history survey, which included detailed information on the diagnosis of any cancer in the parents of the proband, diagnosis of prostate cancer in male relatives and age at onset of prostate cancer in the proband. A history of vasectomy was also obtained from the proband. The control cases consisted of 935 spouses of the probands who were administered the same questionnaire in an identical fashion. RESULTS Prostate cancer was not significantly associated with other types of cancer in proband parents. The presence of prostate cancer in the father, grandfather or uncle of the proband significantly increased the risk of prostate cancer in proband brothers. Early age at onset in the proband was also associated with an increased risk to the proband brothers. CONCLUSIONS Men with a family history of prostate cancer are at a significantly increased risk for prostate cancer, especially if the affected relative had early onset of cancer. Prostate cancer does not seem to be associated with a higher incidence of other cancers in family members.

Clinical and Pathological Features of Hereditary Prostate Cancer

PURPOSE We determined whether the clinical and pathological features of hereditary prostate cancer differ from those of sporadic prostate cancer. MATERIALS AND METHODS We compared the clinical and pathological features of radical prostatectomy specimens from 50 men with and 50 without a family history of prostate cancer who were matched for age and date of surgery. RESULTS Median serum prostate specific antigen concentration was not significantly different in the 2 groups. Mean Gleason score plus or minus standard deviation in the 50 men with sporadic prostate cancer was 6.2 +/- 1 compared to 5.6 +/- 0.9 in those with hereditary disease (p = 0.008). Of the 50 hereditary and 50 sporadic prostate cancers 35 (70%) and 33 (66%), respectively, were pathologically organ confined (p = 0.69). Median percentage of carcinoma within the gland (determined morphometrically) in men with hereditary disease was 11.4 +/- 8.3 compared to 10.9 +/- 8.9 for those with sporadic cancer (p = 0.63). CONCLUSIONS In our study population hereditary prostate cancers have significantly lower Gleason scores compared to sporadic carcinomas. Otherwise, there appear to be no substantial clinical or pathological differences.

Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies.

PURPOSE We determined if prostate specific antigen (PSA) density and PSA slope alone or in combination could be used to predict which men with persistently elevated serum PSA and prior negative prostate biopsies will have prostate cancer on repeat evaluation. MATERIALS AND METHODS In our PSA-1 data base we identified 327 men 50 years old or older with an initially negative prostate biopsy who had persistent PSA elevation, and compared those who did and did not have prostate cancer on subsequent serial prostatic biopsy. RESULTS Of 70 men with a PSA density of 0.15 or more and PSA slope of 0.75 ng./ml. or more annually compared to 83 with a PSA density of less than 0.15 and PSA slope of less than 0.75 ng./ml. annually 32 (46%) and only 11 (13%), respectively, had prostate cancer on subsequent prostate biopsies (p < 0.0001). In a hierarchical logistic regression analysis PSA density and PSA slope were predictive of prostate cancer on subsequent biopsy (p = 0.001 and 0.03, respectively). PSA density of 0.15 or more alone or PSA slope of 0.75 ng./ml. or more annually alone as the indicator for repeat biopsy would have missed 35 and 40% of cancers, respectively. CONCLUSIONS In men with persistently elevated serum PSA after an initially negative prostate biopsy, PSA density and PSA slope alone or in combination provide useful predictive information about the results of repeat prostate biopsies. However, these parameters are not sufficiently sensitive to identify all patients with detectable prostate cancer.