Prostate cancer is highly predictable: a prognostic equation based on all morphological variables in radical prostatectomy specimens

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Preoperative serum prostate specific antigen does not reflect biochemical failure rates after radical prostatectomy in men with large volume cancers

PURPOSE: We compared pathological findings with prostate specific antigen (PSA) failure rates following radical prostatectomy for large volume cancers (6 cc or greater). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

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.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.     

Prostate cancer detection at low prostate specific antigen

PURPOSE: At low prostate specific antigen (PSA) the indication for prostate biopsy is usually an abnormal digital rectal examination. We evaluate the diagnostic value of PSA, digital rectal examination, transrectal ultrasonography and tumor characteristics at low PSA (0 to 4.0 ng./ml.). We confirm and add to recent evidence that digital rectal examination has a low predictive value and that many significant cancers at this PSA range may be missed. MATERIALS AND METHODS: From 1994 to 1997 a total of 10,523 participants 54 to 74 years old were randomized to screening in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Of the participants 9,211 (87.5%) had PSA less than 4.0 ng./ml., and underwent digital rectal examination and transrectal ultrasonography. Expected rates of prostate cancer detection were calculated using logistic regression analysis. Radical prostatectomy was performed in about half of the 478 men diagnosed with prostate cancer. Tumors were characterized by pT category, Gleason score and cancer volume in 166 processed radical prostatectomy specimens. In 50 of these cases PSA was 0 to 4.0 ng./ml. RESULTS: The positive predictive value of digital rectal examination and transrectal ultrasonography at PSA 0 to 4.0 ng./ml. was only 9.7%. Positive predictive value strongly depended on PSA. Sensitivity was calculated by using estimates of the prevalence of sextant biopsy detectable prostate cancers. Of 760 detectable cancers 478 (67%) were diagnosed irrespective of PSA in men screened with digital rectal examination, transrectal ultrasonography and PSA. Only 127 of 348 detectable prostate cancers (36.5%) were actually diagnosed in men with PSA 2 to 4 mg./ml. The importance of these missed cancers was evaluated with parameters of tumor aggressiveness within PSA ranges. CONCLUSIONS: Approximately half of the tumors missed with PSA 0 to 4 ng./ml. had aggressive characteristics (Gleason score 7 or greater, Gleason 4-5 components) and were organ confined. These tumors should be diagnosed and treated according to the present understanding of their natural history. More sensitive and selective screening strategies are needed. Presently a wrong "window of opportunity" is used for early detection of prostate cancer.     

Impalpable Invisible Stage T1c Prostate Cancer: Characteristics and Clinical Relevance in 100 Radical Prostatectomy Specimens-A Different View

Purpose

We analyzed 100 consecutive radical prostatectomy specimens to evaluate the extent and clinical relevance of the stage T1c cancers discovered.

Materials and Methods

All cases were diagnosed by systematic prostatic puncture biopsies because of abnormal prostate specific antigen (PSA) or PSA density. Surgical specimens were examined with the whole organ multiple step-section technique (4 mm.) to identify primary tumor location (peripheral or transition zone cancer), tumor volume, tumor volume divided by prostate volume (percent tumor volume), Gleason score, pathological T stage and positive surgical margins. Tumors smaller than 0.5 cm.³ and without unfavorable pathology (Gleason score 7 or more, or positive surgical margins) were considered insignificant.

Results

Median patient age, PSA, tumor volume and Gleason score were 64 years, 8.8 micro g./l., 1.6 cm.³ and 6, respectively. Of the specimens 46 (46%) had transition zone cancer that was clinically undetectable due to anterior location, while peripheral zone cancers were small, diffuse, anterolateral or in large glands with low percent tumor volume. Transition zone cancer showed greater PSA, PSA density, tumor volume and percent tumor volume than peripheral zone cancer (p = 0.08, 0.03, 0.0002 and 0.0004, respectively), yet with similar Gleason score (p = 0.4). Of the tumors 34 (34%) were locally advanced (stage pT3 and/or positive surgical margins, mostly anterior in 16 transition zone cancers, and apical or posterolateral in 18 peripheral zone cancers), whereas 22 were insignificant (6 transition and 16 peripheral zone cancers). Prostatic puncture biopsies with a core cancer length of less than 3 mm. could have predicted 18 of 19 insignificant tumors but underestimated 13 (33%) and 6 (17%) significant transition and peripheral zone cancers.

Conclusions

The majority of our stage T1c tumors were significant with a distinguished high incidence of transition zone cancer. Therefore, they were large but occult. Transition zone cancer behaved differently than peripheral zone cancer, and warranted considerations during treatment of stage T1c prostate carcinoma.     

Prospective detection of clinically relevant prostate cancer in the prostate specific antigen range 1 to 3 ng./ml. combined with free-to-total ratio 20% or less: the Aarau experience

PURPOSE: Little is known about the incidence rate and clinical relevance of prostate cancer in a low prostate specific antigen (PSA) level. In a prospective PSA based screening study we investigated the incidence and clinicopathological features of prostate cancer that occurred within PSA range 1 to 3 ng./ml. when the free-to-total ratio was 0.20 or less. MATERIALS AND METHODS: Men participating in the Aarau, Switzerland, section of the European Randomized Study of Screening for Prostate Cancer between October 1998 and July 2000 were included in the study. As a side study, all men with PSA between 1 and 3 ng./ml. and free-to-total ratio 0.20 or less were invited to undergo further evaluation with ultrasound guided sextant prostate biopsy. RESULTS: Overall, 168 (7.8%) participants fulfilled inclusion criteria. A total of 158 (94%) patients underwent prostate biopsy, and prostate cancer was detected in 17 (10.8%). There were no statistically significant differences between prostate cancer and benign prostatic hyperplasia in regard to patient age (60.7 versus 59.8 years), prostate volume (23.9 versus 23.0 cc), PSA (1.98 versus 1.86 ng./ml.), free-to-total ratio (0.161 versus 0.160), PSA density (0.089 versus 0.076 ng./ml.) or PSA transition zone density (0.33 versus 0.24 ng./ml., respectively). Median Gleason score was 5 on prostate biopsy versus 6 on retropubic prostatectomy specimen. Of the 14 patients who underwent surgery there were positive lymph nodes in 1, stage pT3b Gleason 7 disease in 1, and pathologically organ confined Gleason 5 in 2, Gleason 6 in 5 and Gleason 7 in 5. Mean tumor volume was 1.01 cc (range 0.02 to 5.17). There were 2 (14.3%) insignificant (less than 0.2 cc, Gleason grade 3 or less), 1 (7.1%) minimal (less than 0.5cc, Gleason grade 3 or less) and 11 (78.6%) clinically relevant and potentially harmful cancers. CONCLUSIONS: There is a significant number of prostate cancer cases diagnosed at PSA as low as 1 to 3 ng./ml. A majority of these tumors are clinically significant. This free-to-total ratio range may be helpful for identifying prostate cancer. The "window of opportunity" for detection of curable cancer may change in populations with higher life expectancy towards lower PSA. Lack of specificity and characterization of tumor aggressiveness remains an unsolved issue for PSA.     

The independent impact of extended pattern biopsy on prostate cancer stage migration

PURPOSE: There are many factors impacting stage migration for prostate cancer. The number of prostate core biopsies is known to increase detection of prostate cancers. It is still unknown whether the number of biopsies is an independent predictor of tumor size. This is important as a number of studies show that tumor volume is an independent predictor of cancer progression. MATERIALS AND METHODS: Using the University of California, San Francisco Urologic Oncology database, a retrospective review of 378 patients undergoing radical prostatectomy by a single surgeon during 2000 to 2003 was performed. Patient and tumor specific variables including age, prostate specific antigen (PSA), number of biopsies, biopsy Gleason grade, tumor volume in the surgical specimen and surgical specimen tumor grade were studied. Univariate and multivariate statistical methods including multiple and logistic regression were used to characterize patients by the number of biopsy cores. Tests of significance to identify predictors of tumor size were based on the partial F statistic and the likelihood ratio test. RESULTS: A total of 317 eligible patients were studied, of whom 119 had 6 biopsies and 198 had more than 6 biopsies. The 2 groups of patients were evenly matched in terms of age, PSA and Gleason sum, with no statistically significant differences observed. On univariate analysis, mean tumor volume was larger for patients receiving 6 core biopsies vs greater than 6 core biopsies (3.85 vs 2.04 cc, p = 0.0009). Additionally, statistically significant differences were observed when comparing median tumor volumes, as well as excluding extremely large volume tumors. On multivariate analysis the number of biopsies performed (6 vs more than 6), was an independent predictor of tumor size (p = 0.006), controlling for primary Gleason score, Gleason sum, PSA as a continuous or categorical variable, year of biopsy and year of surgery. CONCLUSIONS: The use of extended pattern prostate biopsy templates results in the detection of smaller volume prostate cancers, independent of PSA and Gleason grade. These biopsy templates have contributed to the downward stage migration of prostate cancer detection and may possibly contribute to the risk of over detection.     

Ultrasensitive detection of prostate specific antigen in the followup of 422 patients after radical prostatectomy

PURPOSE: We validated our ultrasensitive prostate specific antigen (PSA) assay based on lyophilization and 4-fold concentration of patient sera with the clinical long-term followup and according to histopathological characteristics of 422 patients treated with radical retropubic prostatectomy for prostate cancer. MATERIALS AND METHODS: Each serum sample was divided into 2 aliquots for standard and 4-fold concentrated (ultrasensitive) detection. Samples were analyzed by the same unmodified DPC-Immulite PSA assay. Biochemical relapse was defined as an increase of at least 0.10 ng./ml. in native serum (equivalent to 0.025 ng./ml. in concentrated serum). Mean followup was 449 days (range 29 to 2,057). Kaplan-Meier analysis of standard and ultrasensitive detection results was done, and findings were correlated with pathological stage, Gleason grade, total cancer volume, Gleason grade 4 cancer volume and margin status. Significance of earlier detection in ultrasensitive versus standard detection was calculated with the log rank (Mantel-Cox) test with p <0.05 considered significant. RESULTS: Of 442 patients 88 (20.8%) experienced biochemical recurrence. Of this cohort 28 (31%) demonstrated early failure on the ultrasensitive assay which was later confirmed on the standard assay, 37 (42%) had failure simultaneously on both assays and 23 (26%) had failure on the ultrasensitive but remained disease-free on the standard assay. Average time for ultrasensitive assay detection of recurrence was 288 days (standard 555). Kaplan-Meier analysis revealed significant advantages in earlier detection of recurrence with the ultrasensitive assay, and close correlation with pathological stage, Gleason grade, margin status and Gleason grade 4 cancer volume. Time advantages of ultrasensitive versus standard detection were greater for advanced cancers (pT3a/b or greater, Gleason 3 + 4 or greater) than for small, low grade tumors. All patients who had positive results on the standard assay had a previous (28) or simultaneous (37) positive ultrasensitive result. With standard detection 25% of all relapses were evident within the first year of surgery and with ultrasensitive detection the percentage increased to 85.7%. On both assays 334 patients remained free of biochemical recurrence. CONCLUSIONS: Our ultrasensitive PSA assay is useful for early detection of biochemical relapse after radical retropubic prostatectomy. It not only provides the same accuracy as conventional PSA assays but also offers the advantage of detecting recurrence about 300 days earlier. Thus, long-term results of radical retropubic prostatectomy series can be calculated sooner. The clinical impact of this assay will be obvious once curative treatment options are available if applied at the earliest time of evident tumor recurrence.     

Pathological features of prostate cancer detected on initial and repeat prostate biopsy: results of the prospective European Prostate Cancer Detection study

PURPOSE: We evaluated pathological features of prostate cancer detected on repeat prostate biopsy in men with a serum total prostate-specific antigen (PSA) level between 4 and 10 ng/ml who were diagnosed with benign prostatic tissue after an initial biopsy and compared them to those cancers detected on initial prostate biopsy. MATERIALS AND METHODS: In this prospective European prostate cancer detection study, 1,051 men with a total PSA level between 4 and 10 ng/ml underwent transrectal ultrasound (TRUS)-guided sextant biopsy and two additional transition zone biopsies. All subjects whose biopsy samples were negative for prostate cancer (CaP) underwent a repeat biopsy after 6 weeks. Those with clinically localized cancers underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either initial or repeat biopsy and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS: Initial biopsy was positive (CaP) in 231 of 1,051 enrolled subjects and negative (benign histology) in 820 subjects. Of these 820 subjects, CaP was detected in 10% (83/820) upon repeat biopsy. Of cancers detected on initial and repeat biopsy, 148/231 (64%) and 56/83 (67.5%) had clinically localized disease, respectively, and were offered radical prostatectomy. 10/148 (6.7%) and 3/56 (5.3%), respectively, opted for radiation therapy and thus, 138/148 (93.3%) and 53/56 (94.7%), respectively, underwent radical retropubic prostatectomy. There were statistically significant differences with respect to multifocality (P = 0.009) and cancer location (P < 0.001) with cancers on repeat biopsy showing a lower rate of multifocality and a more apico-dorsal location. In contrast, there were no differences with respect to stage (P = 0.2), Gleason score (P = 0.36), percentage Gleason grade 4/5 (P = 0.1), serum PSA (P = 0.62), and patient age (P = 0.517). CONCLUSIONS: At least 10% of patients with negative prostatic biopsy results will be diagnosed with CaP on repeat biopsy. Despite differences in location and multifocality, pathological and biochemical features of cancers detected on initial and repeat biopsy are similar, suggesting similar biological behavior and thus advocating for a repeat prostate biopsy in case of a negative finding on initial biopsy. Cancers missed on initial biopsy and subsequently detected on repeat biopsy are located in a more apico-dorsal location. Repeat biopsies should thus be directed to this rather spared area in order to improve cancer detection rates.     

Radical Prostatectomy for Incidental (Stage T1a–T1b) Prostate Cancer: Analysis of Predictors for Residual Disease and Biochemical Recurrence

Background

Controversies exist about the most appropriate management for patients with incidental prostate cancer after surgery for benign prostatic hyperplasia (BPH).

Objectives

To test the accuracy of preoperative clinical variables in predicting the presence of residual disease and biochemical recurrence in patients with incidental prostate cancer treated with radical retropubic prostatectomy.

Design, Setting, and Participants

We analyzed 126 T1a–T1b prostate cancers diagnosed at surgery for BPH between 1995 and 2007.

Intervention

All patients underwent radical retropubic prostatectomy within 6 mo of surgery for BPH.

Measurements

Univariate and multivariate logistic regression models addressed the association between the predictors (age, prostate-specific antigen [PSA] before and after surgery for BPH, T1a–T1b stage, prostate volume, and Gleason score at surgery for BPH) and the presence of residual cancer at radical retropubic prostatectomy. Cox proportional hazards regression analyses tested the relationship between the same predictors and the rate of biochemical recurrence after radical retropubic prostatectomy.

Results and Limitations

Seventy-five (59.5%) patients were stage T1a and 51 (40.5%) were stage T1b. At radical retropubic prostatectomy, 21 (16.7%) patients were pT0 and seven (5.6%) patients had extraprostatic disease (pT3). PSA before and after surgery for BPH and Gleason score at surgery for BPH were the only independent predictors of residual cancer at radical retropubic prostatectomy (all p < 0.04). Stage (T1a vs T1b) did not predict residual cancer or the rate of biochemical recurrence. With a mean follow-up of 57 mo, the 5- and 10-yr biochemical recurrence-free survival rates were 92% and 87%, respectively. PSA after surgery for BPH and Gleason score at surgery for BPH were the only significant multivariate predictors of biochemical recurrence (all p < 0.04). The main limitation of this study is the requirement of an external validation before implementation of the clinical recommendations.

Conclusion

PSA measured before and after surgery for BPH and Gleason score at surgery for BPH were the only significant predictors of the presence of residual cancer at radical retropubic prostatectomy. PSA measured after surgery for BPH and Gleason score at surgery for BPH were the only independent predictors of biochemical recurrence after radical retropubic prostatectomy.     

Biochemical recurrence following radical prostatectomy: a comparison between prostate cancers located in different anatomical zones

BACKGROUND: To assess whether differences of biochemical recurrence after radical prostatectomy exist between prostate cancers located in the transition zone (TZ) and peripheral zone (PZ). METHODS: The 5-year biochemical recurrence rate of 307 patients was evaluated. A serum prostate specific antigen (PSA) level > or =0.1 ng/ml was defined as biochemical failure. Cancers were characterized by the location of the largest tumor area as TZ or PZ cancers. Pure PZ cancers were matched to TZ cancers by comparable pathological tumor stage, Gleason score, and surgical margin status. RESULTS: In 63 (20.5%) patients the largest tumor area was located in the TZ. A Kaplan-Meier analysis of the matched pairs calculated an 80% actuarial cure rate of TZ cancers compared to 89% of pure PZ cancers (log-rank test P = 0.742). CONCLUSIONS: TZ and pure PZ cancers matched by comparable pathological tumor stage, Gleason score, and surgical margin status showed no statistical difference in regard to biochemical cure following radical prostatectomy.     

A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate

To determine the characteristics of transition zone and peripheral zone prostate cancer, we examined a series of 42 stage A and 54 stage B radical prostatectomy specimens with particular attention to the number of separate foci of cancer, zone of origin, volume and grade of each focus, and presence of severe intraductal dysplasia (high grade prostatic intraepithelial neoplasia), extra-capsular extension and seminal vesicle invasion associated with cancer in each zone. We found that there were fundamental differences between transition zone and peripheral zone cancers, and that the features that characterize these tumors were apparent in stages A and B disease. Although the total tumor burden was similar in stages A (3.98 cc) and B (4.56 cc) disease, stage A cancer tended to be multifocal (3.1 tumors per prostate) and more diffuse. While 81% of stage A prostate specimens contained a tumor of transition zone origin and 93% had cancer of peripheral zone origin, transurethral resection of the prostate sampled a transition zone cancer in 77% and a peripheral zone cancer in 31% (8% had both types). Stage B cancer tended to be more focal (2.3 cancers per prostate). All stage B prostate specimens contained a peripheral zone cancer and 43% had a transition zone cancer as well. In only 1 stage B cancer patient was the transition zone tumor the palpable or index cancer. In stages A and B disease, peripheral zone tumors were less well differentiated (median Gleason sum 6 and 7) than transition zone tumors (5 and 5, respectively) and more likely to extend through the capsule (44% versus 11%). Seminal vesicle invasion arose from 19% of the peripheral zone but none of the transition zone cancers. Peripheral zone tumors were almost always (93%) associated with high grade prostatic intraepithelial neoplasia, while none of the transition zone cancers was so associated. For peripheral zone disease there was a moderate correlation between volume and grade (tau = 0.46, p less than 0.001) so that the larger the tumor the higher the Gleason sum but within transition zone disease this correlation was poor (tau = 0.23) and not statistically significant (p greater than 0.05). Extracapsular extension occurred at a smaller volume with peripheral zone cancer (mean 3.86, minimum 0.06 cc) than transition zone cancer (mean 4.98, minimum 0.39 cc). Cancer that arises in the transition zone appears to have a different histogenesis, is associated with more favorable pathological features and may have less malignant potential than tumors that arise in the peripheral zone.     

Limitations of Serum Prostate Specific Antigen in Predicting Peripheral and Transition Zone Cancer Volumes as Measured by Correlation Coefficients

Purpose

We reexamined the relationship between preoperative serum prostate specific antigen (PSA) and prostate cancer volume in 290 patients who underwent radical prostatectomy.

Materials and Methods

Serum samples from 290 consecutive patients were remeasured with the automated monoclonal-monoclonal Tosoh AIA-600 assay. These values were correlated with individual cancer volume by measuring Pearson correlation coefficients (r).

Results

Cancer was noted in the transition zone in 31 patients and in the peripheral zone in 259. Of the peripheral zone cancers 133 (51.4 percent) were organ confined and 126 (48.6 percent) were nonorgan confined, including 12 (9.5 percent) with histologically confirmed lymph node metastasis (stage D1). The 259 peripheral zone cancers had a correlation coefficient with PSA (r = 0.499, p less than 0.0001). After distributing the 259 cases into cancer volume groups we found a large overlap in mean preoperative serum PSA, including 65 with 50 percent or greater Gleason grade 4 or 5 disease (r = 0.508). The correlation coefficients of cancer volume with PSA in 133 organ confined cancers, 114 nonorgan confined cancers without lymph node metastases and 12 nonorgan confined cancers with positive lymph nodes were 0.382, 0.438 and 0.363, respectively. The 31 transition zone cancers showed a correlation coefficient with PSA (r = 0.81). After excluding 2 cases with extreme PSA and cancer volume the correlation coefficient decreased (r = 0.077).

Conclusions

Even when remeasured with an automated monoclonal-monoclonal assay serum PSA alone is unable to predict preoperatively cancer volume or distinguish between organ and nonorgan confined cancer in peripheral and transition zone tumors of the prostate.     

CLASSIFICATION OF LOCALIZED UNTREATED PROSTATE CANCER BASED ON 791 MEN TREATED ONLY WITH RADICAL PROSTATECTOMY: COMMON GROUND FOR THERAPEUTIC TRIALS AND TNM SUBGROUPS

Purpose

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.

Materials and Methods

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 [dagger] 0.07 ng./ml. or greater and rising. T1c was defined as impalpable cancer.[dagger] TOSOH Medics, Foster City, California.

Results

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.

Conclusions

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.     

Is low serum free testosterone a marker for high grade prostate cancer?

PURPOSE: The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS: After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS: In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.     

Does the Tertiary Gleason Pattern Influence the PSA Progression-Free Interval after Retropubic Radical Prostatectomy for Organ-Confined Prostate Cancer?

INTRODUCTION: The Gleason sum is an important prognostic parameter for patients treated with radical prostatectomy for localized prostate cancer. However, frequently more than two predominant Gleason patterns are present in one specimen. In this study we investigated the prognostic significance of tertiary Gleason patterns in radical prostatectomy specimens. PATIENTS AND METHODS: Between 1994 and 2001, 277 patients underwent radical retropubic prostatectomy (RRP) for clinically localised prostate cancer in our institute. We collected information on Gleason score and cancer volume (CV) for all tumour localizations, clinical and pathological stage, seminal vesicle invasion (SVI) and extra capsular extension (ECE). In case one pattern was seen in more than 95% of the tumour, this pattern was used both for the primary and secondary Gleason pattern, and any other pattern (actually the secondary pattern) was called tertiary. Charts were examined retrospectively for clinical follow up. PSA progression was defined as two subsequent rising PSA measurements above 0.10 ng/ml. Kaplan-Meier time to PSA progression was compared between patients with and without a tertiary pattern. RESULTS: Overall, of the 223 patients, 106 (48%) were found to have a tertiary pattern, which on average, was 7% of the total tumour volume. Patients with a tertiary pattern had a 5-year risk of PSA progression of 37.3% versus 12.6% in case no tertiary Gleason pattern was present (log rank p=0.0002). There was no prognostic difference between patients with a higher-grade tertiary pattern as compared to those with a lower grade tertiary pattern. CONCLUSIONS: If present, a tertiary Gleason pattern, whether better or worse than the primary or secondary pattern, is an indication for a worse outcome, as indicated by a shorter time to PSA progression. This suggests that tumour multifocality, rather than the presence of a higher-grade tertiary Gleason pattern has prognostic value.     

An artificial neural network for prostate cancer staging when serum prostate specific antigen is 10 ng./ml. or less

PURPOSE: An artificial neural network was developed to improve the prediction of pathological stage before radical prostatectomy based on variables available at biopsy and clinical parameters. MATERIALS AND METHODS: We used the prospectively accrued European prostate cancer detection data base to train an artificial neural network to predict pathological stage in 200 men with serum prostate specific antigen (PSA) 10 ng./ml. or less who underwent radical prostatectomy. Variables included in the artificial neural network were patient age, serum PSA, free-to-total PSA ratio, PSA velocity, transrectal ultrasound calculated total and transition zone volumes with their associated PSA parameters (transition zone PSA density and PSA density), digital rectal examination and Gleason score on biopsy. Two multilayer perceptron neural networks were trained on the remaining variables. Data on the 200 patients were divided randomly into a training set, a test set and a validation or prospective set. RESULTS: Overall classification accuracy of the artificial neural network was 92.7% and 84.2% for organ confined and advanced prostate cancer staging, respectively. For preoperatively predicting local versus advanced stage the area under the ROC curve for the artificial neural network was significantly larger (0.91) compared with logistic regression analysis (0.83), Gleason score (0.69), PSA density (0.68), prostate transition zone volume (0.63) and serum PSA (0.62) (all p <0.01). CONCLUSIONS: The artificial neural network outperformed logistic regression analysis and correctly predicted pathological stage in more than 90% of the validation patients with serum PSA 10 ng./ml. or less based on clinical, biochemical and biopsy data. In the future artificial neural networks may represent a significant step for improved staging of prostate cancer when counseling patients referred for radical prostatectomy or other curative treatments.     

Correlation of serum prostate specific antigen and quantitative immunohistochemistry

PURPOSE: Serum prostate specific antigen (PSA) in patients with prostate carcinoma is influenced by prostate size, transition zone volume, and tumor differentiation and volume. Immunohistochemistry studies have demonstrated an inverse correlation between PSA staining intensity and tumor grade, yet to our knowledge tissue expression of PSA has never been correlated with serum PSA. MATERIALS AND METHODS: In 47 radical prostatectomy cases serum PSA was corrected for gland size and tumor volume. Standard immunohistochemistry staining techniques were applied to specimens using monoclonal antibodies to PSA and cytokeratin CAM5.2. Color images of PSA and CAM5.2 immunohistochemistry stained slides were digitally acquired and analyzed using a standard image analysis system. Representative tumor foci in each slide were imaged with a 20x objective and 10x eyepiece. Staining extent and intensity of the tumor epithelium were measured, and stromal elements and luminal areas were excluded from analysis. For each case quantitative PSA staining intensity was expressed relative to keratin staining in adjacent benign epithelium. RESULTS: Gland volume and tumor volume independently correlated with serum PSA. Furthermore, tissue PSA intensity inversely correlated with histological grade of the tumor (p <0.00001). After gland size, tumor volume and grade were considered, corrected quantitative tissue PSA intensity did not significantly correlate with corrected serum PSA. CONCLUSIONS: Immunohistochemistry expression of tissue PSA in prostate carcinoma cannot be used to explain variations in serum PSA. This discrepancy may relate to differences between the amount of PSA produced by prostatic tumors and the amount secreted, and/or the sensitivity of detecting various tissue isoforms of PSA with immunohistochemistry.     

Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop?

PURPOSE: We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. MATERIALS AND METHODS: In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS: Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p = 0.009) and cancer location (p = 0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p = 0.2), Gleason score (p = 0.3), percent Gleason grade 4/5 (p = 0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p = 0.001 and 0.001), lower rate of grade 4/5 (p = 0.02), and lower volume (p = 0.001 and 0.001) and stage (p = 0.001), respectively. CONCLUSIONS: Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies 1 and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.     

Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis

PURPOSE: Lymphadenectomy for prostate cancer is limited to obturator and external iliac lymph nodes, although the internal lymph nodes represent the primary landing zone of lymphatic drainage. We performed anatomically adequate extended pelvic lymphadenectomy to assess the incidence of lymph node metastasis in cases of clinically localized prostate cancer. MATERIALS AND METHODS: A total of 103 consecutive patients underwent extended pelvic lymphadenectomy at radical retropubic prostatectomy comprising 9 selective fields, namely the external iliac, internal iliac, obturator and common iliac lymph nodes bilaterally, and the presacral lymph nodes. Histopathological findings were compared with serum prostate specific antigen (PSA), histopathological stage, preoperative biopsy and postoperative prostatectomy Gleason score. Extended pelvic lymphadenectomy was compared with radical retropubic prostatectomy and standard lymphadenectomy in 100 consecutive patients in terms of complications, the number of lymph nodes dissected and operative time. RESULTS: There were no significant differences in age, preoperative PSA or mean biopsy Gleason score in patients who underwent extended pelvic and standard lymphadenectomy. Metastases were diagnosed in 27 of the 103 patients (26.2%) who underwent the extended procedure. A mean of 28 lymph nodes (range 21 to 42) were dissected. Metastases were identified in the internal iliac and presacral regions despite negative obturator lymph nodes. Of the 27 patients 1 to 3 lymph nodes involved with metastasis were detected in 15, 9 and 1, respectively. In 26 of the 27 patients (95.8%) with lymph node metastasis PSA was greater than 10.5 ng./ml. and preoperative biopsy Gleason sum was 7 or greater. A low risk of 2% for lymph node disease was noted in patients with serum PSA less than 10.5 ng./ml. and biopsy Gleason sum less than 7. There were no significant differences in regard to intraoperative and postoperative complications, lymphocele formation or blood loss in the 2 groups. CONCLUSIONS: Extended pelvic lymphadenectomy is associated with a high rate of lymph node metastasis outside of the fields of standard lymphadenectomy in cases of clinically localized prostate cancer. Lymphadenectomy including the internal iliac lymph nodes should be performed in all patients with prostate cancer who are at high risk for lymph node involvement, as indicated by PSA greater than 10.5 ng./ml. and biopsy Gleason sum 7 or greater. In the low risk group pelvic lymphadenectomy can be omitted.