Journal Articles

  • Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy. Prostate-specific antigen. Urology Shinghal, R., Yemoto, C., McNeal, J. E., Brooks, J. D. 2003; 61 (2): 380-385


    To characterize a subset of patients with biochemical recurrence after radical prostatectomy but with little, if any, subsequent rise in serum prostate-specific antigen (PSA) and no clinical progression during long-term follow-up.Of a series of 600 patients, 158 with biochemical recurrence after radical prostatectomy were examined. We identified a subset with measurable serum PSA levels during long-term follow-up, but with very low PSA velocity and no clinical recurrence. Serum PSA was measured with the ultrasensitive TOSOH assay with a PSA recurrence defined as a serum PSA of 0.07 ng/mL or greater.We identified 14 patients (8.8% of biochemical recurrences) with a detectable serum PSA level after radical prostatectomy yet without clinical or PSA progression at a mean follow-up after radical prostatectomy of 10.3 years. The mean time to PSA recurrence was 5.8 years, and the mean PSA velocity after recurrence was 0.028 ng/mL/yr. No clinical or pathologic features were found that could be used to identify this subset of patients.A subset of patients with biochemical recurrence after radical prostatectomy will not exhibit a progressive rise in serum PSA or clinical progression at 10 years follow-up. This suggests that serum PSA kinetics should be observed after biochemical recurrence before adjuvant hormonal therapy or radiotherapy.

    View details for PubMedID 12597952

  • Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis PROSTATE Shibata, A., Garcia, M. I., Cheng, I., Stamey, T. A., McNeal, J. E., Brooks, J. D., Henderson, S., Yemoto, C. E., Peehl, D. M. 2002; 52 (4): 269-278


    Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer.We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5.In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables.We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established.

    View details for DOI 10.1002/pros.10119

    View details for Web of Science ID 000177541200003

    View details for PubMedID 12210487

  • Relationship between systematic biopsies and histological features of 222 radical prostatectomy specimens: Lack of prediction of tumor significance for men with nonpalpable prostate cancer JOURNAL OF UROLOGY Noguchi, M., Stamey, T. A., McNeal, J. E., Yemoto, C. M. 2001; 166 (1): 104-109


    Because of the recent increase in nonpalpable prostate cancer (clinical stage T1c) in men, preoperative needle biopsy findings have had an important role for treatment decisions. We examine the correlation among histopathological features of 6 systematic biopsies and radical prostatectomy specimens in which 1 investigator reviewed all histological sections.We studied a total of 450 men with clinical stage T1c prostate cancer from whom needle biopsies were matched with radical prostatectomy specimens, and selected 222 patient biopsies that were obtained from 6 or more separate regions of the prostate. The pretreatment parameters of serum prostate specific antigen (PSA), PSA density, number of positive needle biopsies, distribution of positive cores, linear cancer length, and percent Gleason grade 4/5 on the biopsy were determined and compared with histopathological features of prostate cancer in the radical prostatectomy specimens. All biopsies and radical prostatectomies were evaluated morphologically at the department of urology.Of the 222 men the largest cancer was clinically insignificant in 23 (10%), as measured by a cancer volume of less than 0.5 cc. Cancer volume in the prostatectomy specimen was significantly related to all parameters in the biopsy, with the surprising exception of cancer distribution in the positive biopsies. However, all of these correlations with cancer volume were weak, with Pearson's correlation squared (R(2)) multiplied by 100 less than 10%. Unfortunately, tumor grade on the biopsy agreed with the prostatectomy specimen in only 81 of 222 (36%) cases. Grade assessment with needle biopsy underestimated the tumor grade in 102 (46%) cases and overestimated it in 39 (18%). No single parameter in the biopsy was a predictor of tumor significance, as measured by a cancer volume of greater than 0.5 cc. However, the best model to predict a tumor less than 0.5 cc in volume was the combination of a single positive core with cancer length less than 3 mm. that contained no Gleason grade 4/5. The use of PSA or PSA density in combination with needle biopsy findings did not enhance prediction of tumor significance.These results indicate a weak and disappointing correlation among all pathological features of 6 systematic biopsies and radical prostatectomy specimens. The combination of 1 positive core with cancer length less than 3 mm. that contains no Gleason grade 4/5 is probably the best predictor of prostate cancer less than 0.5 cc in men with nonpalpable tumors, a cancer volume that occurred in only 10% of the 222 (23) men.

    View details for Web of Science ID 000169268700026

    View details for PubMedID 11435833

  • Preoperative serum prostate specific antigen does not reflect biochemical failure rates after radical prostatectomy in men with large volume cancers JOURNAL OF UROLOGY Noguchi, M., Stamey, T. A., McNeal, J. E., Yemoto, C. M. 2000; 164 (5): 1596-1600


    We compared pathological findings with prostate specific antigen (PSA) failure rates following radical prostatectomy for large volume cancers (6 cc or greater).A total of 191 men whose radical prostatectomy specimen had a cancer volume of 6 cc or greater were followed for a mean of 3.6 years (range 0.3 to 11.1) and 112 (58.6%) had PSA failure (PSA 0.07 ng./ml. or greater and increasing). Percent Gleason grade 4/5 (the Stanford modified Gleason scale), cancer volume, seminal vesicle invasion, regional lymph nodes, capsular penetration, positive surgical margin, location of the largest cancer in the peripheral or transition zone, prostate weight, patient age, preoperative PSA and clinical stage were analyzed using univariate and multivariate Cox proportional hazards analyses.In univariate regression analysis percent Gleason grade 4/5, lymph node involvement, cancer volume, cancer location in the peripheral zone, capsular penetration and positive surgical margins were significant predictors of biochemical failure. Seminal vesicle invasion, preoperative serum PSA, patient age, prostate weight and clinical stage were not statistically significant. Forward stepwise, multivariate analysis showed that percent Gleason grade 4/5 (p <0.0001, relative risk ratio 2.498), cancer location in the peripheral zone (p = 0.0097, 1.887), cancer volume (p = 0.0157, 1.691) and lymph node involvement (p = 0.0317, 1. 666) were the only independent predictors of biochemical failure. When 52 men with organ confined, large volume prostate cancer were analyzed separately, univariate and multivariate analyses showed that only cancer location in the peripheral zone (p = 0.0021, relative risk ratio 13.473) and percent Gleason grade 4/5 (p = 0. 0449, 4.111) were independent predictors of failure.Percent Gleason grade 4/5, cancer location in the peripheral zone, cancer volume and lymph node involvement have prognostic value in large volume prostate cancer. Cancer location in the peripheral zone and percent Gleason grade 4/5 are the most powerful predictors of biochemical failure in men whose cancer is 6 cc or greater and contained in the prostatic capsule. Preoperative serum PSA is not helpful in distinguishing biochemical failure rates in these large volume cancers whether they are organ confined or not.

    View details for Web of Science ID 000089820300030

    View details for PubMedID 11025712

  • Assessment of morphometric measurements of prostate carcinoma volume CANCER Noguchi, M., Stamey, T. A., McNeal, J. E., Yemoto, C. E. 2000; 89 (5): 1056-1064


    The authors have shown that the primary determinants of prostate carcinoma progression are tumor volume and the percent of the tumor comprised of Gleason Grade 4/5 cells. In the current study the authors evaluated six different techniques for the morphometric measurements of prostate carcinoma volume.A computer-assisted image analysis (NIH Image, developed and maintained by the National Institutes of Health, Bethesda, MD) was used to analyze all 108 step-sectioned prostate specimens obtained between January 1 and December 31, 1997. The authors used the Stanford technique of 0.3-cm step-sections, measuring the volume of the tumor at both 0.3-cm and 0.6-cm intervals. The other 4 methods included the authors' previous method based on an earlier image program, the ellipsoidal method (pi / 6 x width x height x length), an estimation of the square area of the largest tumor, and the maximum tumor dimension (MTD).The authors first checked the accuracy of NIH Image analysis by measuring 24 circles of widely different sizes. The mean coefficient of variation was 1.7% and the correlation between the mean circle areas measured by the NIH Image software and true circle area essentially was perfect (correlation coefficient [r] = 1 and r(2) = 0.999; P < 0.0001). In comparison with the authors' original computer image program using 0.3-cm step-sections measured by a different observer, r(2) with the NIH Image analysis was 0.93. Using NIH Image only, the 0.6-cm step-section method missed measurable cancers in 16.7% of 108 radical prostatectomies in comparison with the 0.3-cm step-method. The mean tumor volume with the 0.6-cm section method (P < 0.0001) and the ellipsoidal method (P < 0.05) were significantly higher than with the 0.3-cm section method. r(2) from linear regressions using the 0.3-cm step section method as the standard versus the ellipsoidal method was 0.594, and was 0.89 versus the 0.6-cm step-section method, 0.652 versus the square area estimation, and 0. 527 versus the MTD method.The results of the current study support NIH Image as a powerful software program for the morphometric measurement of prostate carcinoma volume. Pathologic processing with 0.3-cm section slices was found to be more accurate for tumor volume than the 0.6-cm section slices. The ellipsoidal method, the square area of the largest tumor, and the MTD all were found to be inferior to computer-assisted image analysis measurements. In certain clinical situations in which only estimates of tumor volume are required, the square area of the largest tumor appears to be the best choice (r(2) 0.652).

    View details for Web of Science ID 000088941600015

    View details for PubMedID 10964336

  • Modified extrafascial radical retropublic prostatectomy technique decreases frequency of positive surgical margins in T2 cancers < 2 cm(3) EUROPEAN UROLOGY Villers, A., Stamey, T. A., Yemoto, C., Rischmann, P., McNeal, J. E. 2000; 38 (1): 64-73


    In an effort to decrease the frequency of postoperative positive surgical margins (+SM), a modified extrafascial radical prostatectomy technique was developed and evaluated.402 consecutive radical prostatectomy specimens removed for clinical stage T2 cancers from 1987 to 1994 were histologically examined prospectively for tumor volume, extraprostatic extension and +SM. Surgical technique modification was introduced in 1990. We compared the histologic status and biological outcome of the prostatectomy cases in 1987-1989 (n = 166) to those treated from 1990 to 1994 (n = 236).The two series were comparable in (1) clinical stage and preoperative (PSA, (2) tumor volume, grade and location, and (3) capsular penetration, seminal vesicle and lymph node status. +SM fell from 32 to 25% overall, but for 146 (36%) prostates with a tumor volume <2 cm(3), +SM fell from 21 to 6% which was statistically significant. Outcome measured by biological progression showed a decrease from 33% for +SM to 13% for -SM for cases with a tumor volume <2 cm(3). For cancer volumes >2 cm(3), the incidence of +SM did not vary significantly. We describe the anatomic details necessary for exposure of periprostatic fascias and extrafascial dissection at (1) the prostatourethral junction which ensures wide excision of the anterior and apical aspect of the prostate, (2) the posterior and apical area (development of the prerectal space), lateral and posterior areas at the base of the prostate which ensures wide excision of the rectoprostatic fascia (Denonvilliers's fascia) and lateral prostatic fascia.Differences in surgical technique probably accounted for the significant decrease in +SM for those T2 cancers with volumes < or =2 cm(3) which represents 36% of the T2 cancers in our series. Recent screening with PSA (T1c cancers) increases the incidence of these cancers < or =2cm(3). This modified uni- or bilateral anatomic extrafascial prostatectomy with improved +SM and biological progression rates for T2 cases should be evaluated for T1c cases.

    View details for Web of Science ID 000087826600010

    View details for PubMedID 10859444

  • An analysis of 148 consecutive transition zone cancers: Clinical and histological characteristics JOURNAL OF UROLOGY Noguchi, M., Stamey, T. A., McNeal, J. E., Yemoto, C. E. 2000; 163 (6): 1751-1755


    To improve our understanding of transition zone cancer in terms of the diagnosis and biological behavior we examined all morphological and clinical variables in 148 consecutive cases of untreated transition zone cancer after radical retropubic prostatectomy. We matched 79 cases by total cancer volume to 79 of pure peripheral zone cancer with no secondary tumors.Using the Stanford technique of prospective 3 mm. step sections we identified 175 of 996 men (18%) with untreated transition zone cancer after radical retropubic prostatectomy who had the largest cancer volume in the transition zone. We excluded 27 patients from study due to previous transurethral prostatic resection or incomplete data. Preoperative serum prostate specific antigen (PSA) was determined by the Tosoh AIA-600 PSA assay. Postoperatively a PSA of 0.07 ng./ml. and increasing represented biochemical failure when the assay was done in the ultrasensitive mode.Of the 148 cases of transition zone cancer 80% had organ confined disease, 70% stage T1c impalpable disease, 63% a positive initial prostatic biopsy, 62% unilateral cancer in the transition zone, 52% a secondary tumor only in the peripheral zone, 61% serum PSA 10 ng./ml. or greater preoperatively, 36% cancer volume greater than 6 cc and 24% at least 50% Gleason grade 4/5 cancer. Only 20% of the tumors were located in the proximal third of the transition zone near the bladder. The number of secondary tumors in the transition zone ranged from 1 to 12 (median 3) and secondary tumor volume ranged from 0.01 to 4.8 cc (median 0.6). Mean distance plus or minus standard deviation from the posterior prostatic capsule to the posterior border of the transition zone cancer was 12. 0 +/- 7.6 mm. (median 12.3). While only 15% of patients had capsular penetration, 29% had anterior positive surgical margins, 2.7% seminal vesicle invasion and 3.4% lymph node metastasis. When 79 transition zone cancers were matched by volume with 79 peripheral zone cancers, there were no differences in percent Gleason grade 4/5, serum PSA or prostate weight, although differences in clinical stage T1c to T2c and organ confined cancer were highly significant (p <0.0001). Kaplan-Meier curves showed that at 5 years of followup 49.2% of the men with peripheral zone cancer had undetectable PSA compared with 71.5% of those with transition zone cancer (log rank test p = 0.0002).Our report should make it easier to diagnose transition zone cancer. The 72% biochemical PSA cure rate is significantly higher than the 49% cure rate for peripheral zone cancer. Since cancer volume and percent Gleason grade 4/5 disease were the same in these 2 groups matched by cancer volume, the differences in behavior of peripheral and transition zone cancers must be sought at the molecular level unless anatomical location alone explains the differences in progression. Pathologists should differentiate transition from peripheral zone cancer when analyzing radical prostatectomy specimens.

    View details for Web of Science ID 000086984900034

    View details for PubMedID 10799175

  • Prostate cancer is highly predictable: A prognostic equation based on all morphological variables in radical prostatectomy specimens JOURNAL OF UROLOGY Stamey, T. A., Yemoto, C. M., McNeal, J. E., Sigal, B. M., Johnstone, I. M. 2000; 163 (4): 1155-1160


    We determine whether biochemical prostate specific antigen (PSA) failure can be accurately predicted from preoperative serum PSA combined with 6 morphological variables from radical retropubic prostatectomy specimens in men with peripheral zone cancers. The unexpected limitation imposed by preoperative serum PSA on biochemical failure led us to compare peripheral zone to transition zone cancers.A total of 326 peripheral zone and 46 transition zone cancers treated only with radical retropubic prostatectomy were followed for a minimum of 3 years (mean and median greater than 5). All prostates were sectioned at 3 mm. intervals and morphological variables were quantitated using the Stanford technique. Biochemical failure was defined as serum PSA 0.07 ng./ml. or greater and increasing. Multivariate logistic regression was used to identify variables with the most independent influence on biochemical failure and derive a clinical equation to predict failure in peripheral zone cancers. The validity of the predictive equation was assessed by out of sample validation and cross validation techniques. The 46 transition zone cancers were compared to the 326 peripheral zone cancers by Student's t and Wilcoxon tests.Of the peripheral zone failures 60% occurred in the first year after radical retropubic prostatectomy and 95% had occurred by the end of year 4. The highest preoperative serum PSA was 23 ng./ml. among the 181 men biochemically free of disease. Only 15.8% of 57 men with PSA greater than 15 ng./ml. were biochemically disease-free. For the 48 transition zone cancers cure rates were independent of serum PSA with 6 men having PSA greater than 50 ng./ml. Biochemical disease-free status was noted in 80% of transition zone compared to 56% of peripheral zone cancers (p = 0.0009). The most important variables predicting biochemical disease-free status for peripheral zone cancers were percent Gleason grade 4/5, cancer volume, serum PSA and prostate weight. Foci of vascular invasion, intraductal cancer and lymph nodes were less significant variables, and capsular penetration, positive surgical margins and seminal vesical invasion were insignificant. The multivariate logistic equation for predicting failure in peripheral zone cancers was highly accurate and requires only 2 to 3 minutes with a simple calculator.Failure of radical retropubic prostatectomy to cure peripheral zone prostate cancer is highly predictable based on 6 morphological variables from the prostatectomy specimen and serum PSA. The level of serum PSA profoundly limits biochemical cure rates in peripheral zone cancers. Transition zone cancers have a high cure rate, despite high serum PSA and adverse morphological variables. Men with serum PSA greater than 15 and perhaps even greater than 10 ng./ml. have such a low cure rate for peripheral zone cancer that re-biopsy attempts appear indicated to prove a transition zone location or else therapy other than radical retropubic prostatectomy should be sought. Pathologists should indicate whether the primary (largest) cancer is in the peripheral or transition zone to prevent overoptimistic reports of cure with radical prostatectomy procedures, as 85% of all tumors are in the peripheral zone.

    View details for Web of Science ID 000085974000022

    View details for PubMedID 10737486

  • Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: Relationship to transition zone volume JOURNAL OF UROLOGY Stamey, T. A., Yemoto, C. E. 2000; 163 (1): 119-126


    We evaluated the relative usefulness of total, free and complexed serum prostate specific antigen (PSA), and their ratios for distinguishing positive from negative biopsy of prostates in a university referral practice.We compared 90 consecutive men who had 2 sets of 6 negative systematic biopsies with 70 who had at least 5 mm. of prostate cancer in systematic biopsies during the same period at our institution. Total prostate and transition zone volumes were determined by transrectal ultrasound. The Bayer, DPC and Hybritech assays were performed to measure total, free and complexed serum PSA. Receiver operating characteristics curves were constructed for all forms of serum PSA and their ratios as well as prostate size to distinguish true positive (sensitivity) from false-positive (1 minus specificity) fractions.Complexed PSA was only marginally better than total serum PSA. Free-to-total, complexed-to-total and prostate size had highly significant areas under the curves of greater than 80%. Free PSA only was better than complexed or total PSA. When factored by prostate volume, total PSA performed as well as the PSA ratios, and transition zone volume was consistently better than total prostate volume. DPC free-to-total ratios were equivalent to Hybritech ratios in all respects.Complexed PSA is only marginally better than total PSA for distinguishing negative from positive biopsy of prostates. It is inferior to free PSA and far less useful than free-to-total or complexed-to-total ratios. Prostate size is a decisive variable in men in whom we avoided the expected 25% false-negative biopsy rate in terms of specificity and hopefully avoided insignificant cancer in terms of sensitivity. In the future the performance of PSA serum markers should be related to a transition zone volume of less than 20, 20 to 60 and greater than 60 gm. when comparing assays to each other.

    View details for Web of Science ID 000084324900036

    View details for PubMedID 10604328

  • Biological determinants of cancer progression in men with prostate cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stamey, T. A., McNeal, J. E., Yemoto, C. M., Sigal, B. M., Johnstone, I. M. 1999; 281 (15): 1395-1400


    The recent increase in ability to diagnose prostatic adenocarcinoma has created a dilemma for treatment decisions.To determine whether prostate cancer progression is associated with a modified version of the Gleason grading system together with selected morphologic and clinical variables.Retrospective analysis of a cohort of patients with peripheral zone prostate cancers who underwent surgery between August 1983 and July 1992.University hospital.Radical prostatectomy specimens from 379 men treated only by surgical excision were prospectively studied for 8 morphologic variables using previously standardized techniques. Variables were percentage of each cancer occupied by Gleason grade 4/5 (% Gleason grade 4/5, the Stanford modified Gleason scale), cancer volume, vascular invasion, lymph node involvement, seminal vesicle invasion, capsular penetration, positive surgical margin, prostate weight, and preoperative prostate-specific antigen (PSA) level.Biochemical progression of prostate cancer as indicated by serum PSA level of 0.07 ng/mL and increasing.Cancer grade expressed as % Gleason grade 4/5 and cancer volume were highly predictive of disease progression. In a Cox proportional hazards model that included % Gleason grade 4/5, the traditional Gleason score was not an independent predictor of treatment failure. Positive lymph node findings and intraprostatic vascular invasion were the only other variables that remained significant at the .01 level.The % Gleason grade 4/5, cancer volume, positive lymph node findings, and intraprostatic vascular invasion were independently associated with prostate cancer progression, defined by an increasing PSA level. Techniques to accurately measure cancer volume and % Gleason grade 4/5 are needed to better predict which patient will experience cancer progression. The commonly accepted predictors of progression-capsular penetration and positive surgical margins-were not independently predictive of failure after radical prostatectomy.

    View details for Web of Science ID 000079701000029

    View details for PubMedID 10217055

  • Histological and clinical findings in 896 consecutive prostates treated only with radical retropubic prostatectomy: Epidemiologic significance of annual changes JOURNAL OF UROLOGY Stamey, T. A., Donaldson, A. N., Yemoto, C. E., McNeal, J. E., Sozen, S., Gill, H. 1998; 160 (6): 2412-2417


    Recognizing that the unprecedented increase in new cases of prostate cancer between 1988 and 1996 actually peaked in 1992 and has now returned to baseline, we examined our clinical and histological database for annual trends in 896 consecutive men treated only with radical prostatectomy for clinical stages T1c to T2c from 1988 to 1996.All radical prostatectomy specimens were examined prospectively in 3 mm. step sections by 1 pathologist. Using multiple logistic regression for dichotomous variables and multiple linear regression for continuous variables, both corrected for age, we assessed the annual trends for significant changes in T1c versus T2 clinical stages, preoperative serum prostate specific antigen (PSA), cancer volume, percent Gleason grade 4/5 in the cancer, location of the cancer in the transition or peripheral zone, organ confined status, seminal vesicle invasion, positive surgical margins, prostate weight and presence of clinically insignificant cancers (less than 0.5 cc in volume).There were no significant annual changes in the proportion of percent Gleason grade 4/5 cancer, serum PSA, prostate weight or clinically insignificant cancers less than 0.5 cc, and the annual changes for cancer volume were only of moderate significance. T1c cancers increased from 10% in 1988 to 73% in 1996 (p=0.0001), organ confined cancers from 40 to 75% (p=0.0001) and transition zone cancers from 10 to 21% (p=0.003). Seminal vesicle invasion decreased from 18 to 5% (p=0.001) and positive surgical margins from 30 to 14 (p=0.006). Mean patient age changed from 65 to 62 years (p=0.0001).We believe that the extraordinary rise and fall in prostate cancer detection rates from 1990 to 1994 primarily removed previously undetected T2 cancers from the pool at large, leaving impalpable T1c cancers as the primary reservoir of prostate cancers in the United States. Importantly, cancer volume, percent Gleason grade 4/5 cancer, serum PSA and cancers less than 0.5 cc have not had a highly significant change during these critical 9 years. These data argue strongly that current PSA testing has not resulted in the detection of clinically insignificant cancers, and that PSA screening should be expanded and not restricted.

    View details for Web of Science ID 000076876300009

    View details for PubMedID 9817394

  • Classification of localized untreated prostate cancer based on 791 men treated only with radical prostatectomy: Common ground for therapeutic trials and TNM subgroups JOURNAL OF UROLOGY Stamey, T. A., Sozen, T. S., Yemoto, C. M., McNeal, J. E. 1998; 159 (6): 2009-2012


    We examined cancer volume, percent Gleason grade 4/5 cancer, cancer location (peripheral versus transition zone), capsular penetration and biochemical cure rates in men undergoing radical prostatectomy to determine differences among clinical stages T1c, T2a, T2b and T2c.Detailed chart reviews confirmed the precise clinical stages assigned to 791 consecutive men treated only with radical prostatectomy. All prostates were examined prospectively by the Stanford technique of 3 mm. step sections. For biochemical cure rates a subset of 366 men were followed for a minimum of 5 years. Failure was defined as prostate specific antigen Tosoh 0.07 ng./ml. or greater and rising. T1c was defined as impalpable cancer.T1c and T2a stages had half as much cancer volume as T2b and T2c cancers, 10 versus 25% Gleason grade 4/5 and half as much capsular penetration (30 versus 61%). Biochemical cure rates were 70 and 72% for T1c and T2a compared to 37 and 27% for T2b and T2c, respectively. Of T1c cancers 25% were in the transition zone compared to 7.9 to 9.9% of T2a to c cancers.T1c cancers are similar to T2a cancers in tumor volume and percent Gleason grade 4/5, the primary determinants of therapeutic failure. Minimal 5-year cure rates for T1c and T2a cancers are similar. Transition zone cancers are 2.5 times more common in T1c cancers than in palpable T2 tumors. T2a cancers like T1c cancers are highly favorable tumors and should be retained in TNM classifications. These data suggest that the 4 clinical stages of T1c to T2c can serve as a valid basis for comparing different therapeutic strategies.

    View details for Web of Science ID 000073584400071

    View details for PubMedID 9598508

  • Significance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY McNeal, J. E., Yemoto, C. E. 1996; 20 (11): 1351-1360


    Histologically demonstrable vascular invasion by tumor has been reported as an index of poor prognosis correlating with increased probability of metastasis in many types of cancer other than prostatic. We quantitated vascular invasion foci in 357 radical prostatectomy specimens and developed improved criteria for their diagnosis and their distinction from fixation artifact. Vascular invasion foci were found in 7% of cancers less than 4 cc in volume and 24% of larger cancers. Most foci were selectively located either near the basal end of the cancer or near the transition zone border. Correlations among multiple morphologic variables showed significant correlation of vascular invasion only with the presence of intraductal carcinoma. The only statistically significant independent predictors of disease progression (serum prostate-specific antigen elevation) were vascular invasion, carcinoma grade, and cancer volume. Our findings suggest that further study of vascular invasion foci may disclose additional information about the biologic features of local and distant spread of prostatic carcinoma.

    View details for Web of Science ID A1996VQ50300006

    View details for PubMedID 8898839

  • Spread of adenocarcinoma within prostatic ducts and acini - Morphologic and clinical correlations AMERICAN JOURNAL OF SURGICAL PATHOLOGY McNeal, J. E., Yemoto, C. E. 1996; 20 (7): 802-814


    Malignant epithelial masses within prostatic duct lumens have been equated with several conflicting entities, including Gleason cribriform grade 3 carcinoma and cribriforming dysplasia. We identified 51 radical prostatectomy cancers containing intraductal lesions among 130 cases, with total cancer volumes between 4 and 10 cc. Such lesions with duct lumen-spanning septa or masses were rare in areas away from invasive cancer (22 foci), while dysplasia (prostatic intraepithelial neoplasia) was common (1,490 foci). Consequently, these lesions were interpreted as being part of the evolution of invasive carcinoma rather than precursors; they were designated "intraductal carcinoma" as distinct from dysplasia. Intraductal cancer areas within invasive carcinoma usually represented cancer extension within the branches of a single segment of the duct-acinar system from near the urethra to the gland capsule. In 51% of cases with intraductal spread, the invasive component produced large ( > 0.5 mm) tumor masses in perineural spaces, which in turn correlated strongly with extensive capsule penetration and frequent positive surgical margins selectively at the superior nerve pedicle. The amount of grade 4/5 cancer, the amount of intraductal carcinoma, and the large perineural tumor mass appeared to be related to postprostatectomy progression of cancer, as measured by elevation of ultrasensitive serum prostate-specific antigen. It was concluded that intraductal prostatic adenocarcinoma is a common morphologic entity with precisely defined histologic criteria and a unique biologic significance, as reflected by an enhanced capacity for extensive spread within ducts and perineural spaces. It was proposed that the diversity of diagnoses attached to most cribriform malignant lesions can be unified by the concept of this single entity.

    View details for Web of Science ID A1996UU25500003

    View details for PubMedID 8669528

  • The periurethral glands do not significantly influence the serum prostate specific antigen concentration JOURNAL OF UROLOGY Oesterling, J. E., Tekchandani, A. H., Martin, S. K., Bergstralh, E. J., Reichstein, E., Diamandis, E. P., Yemoto, C., Stamey, T. A. 1996; 155 (5): 1658-1660


    The periurethral glands are known to produce prostate specific antigen (PSA). With ultra-sensitive assays now routinely available, it is necessary to determine if the periurethral glands significantly influence serum PSA concentration after radical prostatectomy.Serum PSA levels of 46 men, 51 to 89 years old (median age 67) who underwent radical cystoprostatectomy and total urethrectomy, were compared with those of 92 men 46 to 91 years old (median age 67) who underwent radical cystoprostatectomy only. All men had transitional cell carcinoma of the bladder without gross or microscopic evidence of prostate cancer and all underwent ileal conduit diversion. Serum was obtained at least 1 year postoperatively. Each specimen was analyzed using the Tosoh, Immulite, and Yu and Diamandis ultra-sensitive PSA assays with analytical detection limits of 0.02 ng./ml., 0.004 ng./ ml. and 0.002 ng./ml., respectively.Median PSA for the radical cystoprostatectomy with urethrectomy group was 0.00 ng./ml. (range 0.00 to 0.14) for each of the 3 assays. For the radical cystoprostatectomy only group the median Tosoh and Immulite PSA assay levels were 0.01 ng./ml. (range 0.00 to 0.22), and median Yu and Diamandis PSA assay level was 0.00 ng./ml. (range 0.00 to 0.31).The greatest difference in median PSA levels that could be found between men with and without periurethral glands when using 3 different ultra-sensitive assays was 0.01 ng./ml., indicating that the periurethral glands do not have a clinically significant effect on serum PSA concentration after radical prostatectomy. Thus, a serum PSA level above the residual cancer detection limit following radical prostatectomy, even if obtained with a ultra-sensitive assay, reflects either malignant or benign residual prostatic tissue, rather than the presence of periurethral glands.

    View details for Web of Science ID A1996UF00800034

    View details for PubMedID 8627847

  • Prostate specific antigen releases a kinin-like substance on proteolysis of seminal vesicle fluid that stimulates smooth muscle contraction JOURNAL OF UROLOGY Fichtner, J., GRAVES, H. C., THATCHER, K., Yemoto, C., Shortliffe, L. M. 1996; 155 (2): 738-742


    We investigated whether purified prostate specific antigen (PSA), a seminal plasma serine protease of the kallikrein enzyme family, is capable of releasing kinin-like peptides from natural substrate glycoproteins in human seminal vesicle fluid.An in vivo rat bladder model was used to monitor for release of substances capable of inducing smooth muscle contractions. Purified PSA, seminal vesicle fluid (SVF) from radical prostatectomy specimens, bradykinin, saline and a bradykinin antagonist were injected intravesically into urethane-anesthetized rats, and the resulting bladder contractions were measured.Injection of either PSA or SVF alone did not induce bladder contractions. Injection of a mixture of SVF and PSA preincubated 15 minutes, however, induced strong bladder contractions (23 +/- 7 cm. H2O) that decreased with time (4 +/- 2 cm. H2O, after 90 minutes). Similar contractions were observed after injection of bradykinin (10(-4) M. = 39 +/- 14, 10(-6) M. = 27 +/- 9, 10(-8) M. = 7 +/- 4 cm. H2O). Addition of a bradykinin antagonist to the PSA-SVF mixture prior to injection blocked the observed bladder contractions (23 +/- 7 cm. H2O before, versus 0.3 +/- 1.2 cm. H2O after adding antagonist).We conclude that PSA produces a kinin-like substance by enzymatic cleavage of glycoproteins in human seminal fluid. This substance induces smooth muscle contractions which can be specifically blocked by addition of a bradykinin antagonist.

    View details for Web of Science ID A1996TP49300104

    View details for PubMedID 8558716



    Patterns of cell proliferation in the prostate were compared between benign epithelium and dysplasia. Proliferating cell nuclear antigen (PCNA) immunostaining was used to quantitate proliferation, and basal cells were tallied separately from secretory cells with the aid of keratin immunostaining. Using a novel technique, absolute cell densities (cells/mm) were determined and used to calculate growth fractions. In benign epithelium, 83% of PCNA+ cells were basal cells, while only 7% of PCNA+ cells in dysplasia were basal cells and there was a clear separation between groups. This dramatic shift of the proliferative compartment to the secretory cells in dysplasia was accompanied only by a moderate increase in overall secretory cell density and moderate reduction in basal cell density, but these ranges overlapped those of benign epithelium. The median PCNA+ secretory cell "growth fraction" was 0.12% in benign epithelium and 1.06% in dysplasia. The findings presented give further support to the concept that dysplasia represents an evolutionary stage in the malignant transformation of prostatic epithelium. The patterns of change in PCNA immunostaining may reflect certain aspects of the biologic nature of malignant transformation.

    View details for Web of Science ID A1995TF41400004

    View details for PubMedID 7479393

Conference Proceedings

  • Preoperative serum prostate specific antigen levels between 2 and 22 ng./ml. correlate poorly with post-radical prostatectomy cancer morphology: Prostate specific antigen cure rates appear constant between 2 and 9 ng./ml. Stamey, T. A., Johnstone, I. M., McNeal, J. E., Lu, A. Y., Yemoto, C. M. ELSEVIER SCIENCE INC. 2002: 103-111


    Serum prostate specific antigen (PSA) is widely used as a guide to initiate prostatic biopsies and to follow men older than 50 years old with and without prostate cancer. However, benign prostatic hyperplasia (BPH) is a common cause of serum PSA values between 2 and 10 ng./ml. A better understanding of the relationships among serum PSA, prostate cancer and BPH is important.A total of 875 men underwent radical prostatectomy at our institution between December 1984 and January 1997. Of these men 784 had a serum PSA of 2 to 22 ng./ml., including 579 with the largest cancer located in the peripheral zone of the prostate. Of the 579 men 406 had serum PSA followups for greater than 3 years after radical prostatectomy. We examined Pearson correlations (R2) between preoperative serum PSA, and the volume of Gleason grades 4/5 and 3 to 1 cancer in 784 men, separating peripheral zone from transition zone cancers. We used broken line regression with break points of 7 and 9 ng./ml. preoperative PSA to summarize the relationship of each PSA doubling to 5 different morphological variables in 579 men with peripheral zone cancer. A 9 ng./ml. break point was used for prostate weight. Trend summaries with a local regression line for the relationships between 6 morphological variables and PSA were superimposed on full scatterplots of the 579 men with PSA less than 22 ng./ml. Cox proportional hazard models were used to examine 5-year PSA failure-free probabilities based on 406 men with minimal PSA followups greater than 3 years at break points of 7 to 9 ng./ml. PSA.Pearson correlation between cancer volume and preoperative serum PSA in 875 men was weak (r2 = 0.27) and driven by large cancers with serum PSA greater than 22 ng./ml. For peripheral zone cancer the overall R2 x 100 for 641 men with low and high grade cancer was 10% and only 3% for low grade cancer, that is almost no PSA produced by these peripheral zone cancers enters the serum. All morphological variables changed at rates of doubtful medical significance below a PSA of 7 to 9 ng./ml. but at rates that were significantly worse above 9 ng./ml. R2 for these relationships was never greater than 15%. Large individual morphological variations at all levels of PSA emphasize the serious limitation of PSA as a predictor of prostate cancer morphology. Below 9 ng./ml. prostate weight increased by 21% for each doubling of PSA but above 9 ng./ml. the increase was only 4.8%.Preoperative serum PSA has a clinically useless relationship with cancer volume and grade in radical prostatectomy specimens, and a limited relationship with PSA cure rates at preoperative serum PSA levels of 2 to 9 ng./ml. Trend summaries for prostate weight on broken line regression showed that below 9 ng./ml. BPH is a strong contender for the cause of PSA elevation, constituting the primary cause of the over diagnosis of prostate cancer.

    View details for Web of Science ID 000172726200033

    View details for PubMedID 11743285

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