CONTEMPORARY UPDATE OF PROSTATE CANCER STAGING NOMOGRAMS (PARTIN TABLES) FOR THE NEW MILLENNIUM

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1 RAPID COMMUNICATION CME ARTICLE CONTEMPORARY UPDATE OF PROSTATE CANCER STAGING NOMOGRAMS (PARTIN TABLES) FOR THE NEW MILLENNIUM ALAN W. PARTIN, LESLIE A. MANGOLD, DANA M. LAMM, PATRICK C. WALSH, JONATHAN I. EPSTEIN, AND JAY D. PEARSON ABSTRACT Objectives. We previously presented nomograms combining preoperative serum prostate-specific antigen (), clinical (TNM) stage, and biopsy Gleason score to provide the likelihood of various final pathologic stages at radical retropubic prostatectomy. The data for the original nomograms were collected from men treated between 1982 and During the past 10 years, the stage at presentation has shifted, with more men presenting with Stage T1c, Gleason score 5 to 6, and serum levels less than 10.0 ng/ml. In this work, we update the Partin Tables with a more contemporary cohort of men treated since 1994 and with revised and Gleason categories. Methods. Multinomial log-linear regression analysis was used to estimate the likelihood of organ-confined disease, extraprostatic extension, seminal vesicle or lymph nodal status from the preoperative stratified as 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10.0, and greater than 10 ng/ml, clinical (AJCC-TNM, 1992) stage (T1c, T2a, T2b, or T2c), and biopsy Gleason score stratified as 2 to 4, 5 to 6, 3 4 7, 4 3 7, or 8 to 10 among 5079 men treated with prostatectomy (without neoadjuvant therapy) between 1994 and 2000 at Johns Hopkins Hospital. The average age was 58 years. Results. In this cohort, more than 60% had T1c, more than 75% had Gleason score of 6, more than 70% had greater than 2.5 and less than 10.0 ng/ml, and more than 60% had organ-confined disease. Nomograms of the robust estimated likelihoods and 95% confidence intervals were developed from 1000 bootstrap analyses. The probability of organ-confined disease improved across the groups, and further stratification of the Gleason score and level allowed better differentiation of individual patients. Conclusions. These updated Partin Tables were generated to reflect the trends in presentation and pathologic stage for men newly diagnosed with clinically localized prostate cancer at our institution. Clinicians can use these nomograms to counsel individual patients and help them make important decisions regarding their disease. UROLOGY 58: , , Elsevier Science Inc. This study was supported by Prostate SPORE grant CA and NCI Early Detection Research Network (EDRN) grant UO1 CA From the James Buchanan Brady Urological Institute and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland and Merck Research Laboratories, Rahway, New Jersey Reprint requests: Alan W. Partin, M.D., Ph.D., Brady Urological Institute, Johns Hopkins Hospital, 600 North Wolfe Street, Marburg 205A, Baltimore, MD Submitted: August 1, 2001, accepted (with revisions): August 16, 2001 The American Cancer Society reported this year a continued decrease in prostate cancer death rates, with an estimate that 75% of newly diagnosed patients this year will present with either local or regional disease. 1 This trend or stage migration, whether the result of improved early detection programs or a change in the biology of the disease, has nonetheless resulted in a dramatic shift in the stage at presentation for men newly diagnosed with prostate cancer. More men are presenting with serum prostate-specific antigen () levels between 2.5 and 10.0 ng/ml, predominately Gleason scores of 6, normal digital rectal examinations (clinical Stage T1c), and, most importantly, with localized organ-confined disease (more than 75% in our recent series). Our present staging algorithms, 2 4 which were based on data collected primarily from cases treated before 1995, less accurately reflect the presentation of the contemporary cohort of men presenting today with prostate cancer. In this work, we update the Partin Tables 2001, ELSEVIER SCIENCE INC /01/$20.00 ALL RIGHTS RESERVED PII S (01)

2 with a more contemporary cohort of men treated since 1994 with revised and Gleason categories. MATERIAL AND METHODS PATIENTS Between 1994 and 2000, 5079 men with clinically localized prostate cancer and no neoadjuvant hormonal or radiation therapy underwent radical retropubic prostatectomy (RRP) and a staging pelvic lymphadenectomy at the Johns Hopkins Hospital by 1 of 11 attending surgeons. INCLUSION CRITERIA Men enrolled in this cohort had (a) a preoperative monoclonal serum level on an ambulatory basis before RRP and at least 4 weeks after the prostate biopsy, (b) a biopsy histologic grade (Gleason score), and (c) a clinical stage assigned by the attending physician (AJCC-TNM, 1992) of T1c, T2 (a-c). Men were excluded because of a lack of this information or if they received preoperative neoadjuvant hormonal therapy. Although a very rare occurrence (0.25%), men with grossly positive pelvic lymph nodes who did not undergo surgery were also excluded from this analysis. PATHOLOGIC EXAMINATION All pelvic lymph nodes removed at surgery were sectioned and examined for the presence of cancer. Likewise, the surgical specimen, including the prostate and seminal vesicles, was analyzed and the pathologic stage determined as organ-confined if all cancer was confined within the prostate, extraprostatic extension if cancer was evident outside the prostate and the seminal vesicles and the pelvic lymph nodes were free from metastatic disease, positive seminal vesicle involvement if the tumor invaded the muscular wall of the seminal vesicle without lymph nodal involvement, and lymph node involvement if the pelvic lymph nodes were involved with cancer. STATISTICAL ANALYSIS Baseline-category multinomial log-linear regression analysis 5 was performed simultaneously for the four outcomes. The predictor variables were serum total levels before surgery, which were categorically divided into 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10, and more than 10.0 ng/ml, TNM clinical stage (AJCC 1992) as T1c, T2a, T2b, or T2c (categorical), and biopsy Gleason score sum divided categorically as 2 to 4, 5 to 6, 3 4 7, 4 3 7, and 8 to 10. S-Plus for Windows software was used to perform the multinomial log-linear regression analysis. The nomograms were constructed from the robust predicted probabilities and the 95% confidence intervals for the final model that were obtained by repeating the analysis on 1000 bootstrap samples 6 from the original cohort. The bootstrap analyses were performed in S-Plus for Windows. RESULTS PARTICIPANT DEMOGRAPHICS In the study, 5079 men, average age years (range 42 to 74) who fit the enrollment criteria, were consecutively enrolled. Ninety percent of the men were white and 6% African American. Within the groups, 7%, 10%, 27%, 35%, and 21% were within the 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10, and more than 10.0 ng/ml groups, respectively. Biopsy Gleason grades (sum) demonstrated 0.6%, 79%, 13%, 4.4%, and 3% with a Gleason score of 2 to 4, 5 to 6, 3 4 7, 4 3 7, and 8 to 10, respectively. Seventy-five percent of the biopsy Gleason scores were The clinical stage was T1c, T2a, T2b, and T2c in 63%, 32%, 11%, and 3%, respectively. The final pathologic stage demonstrated that 64%, 30%, 4%, and 2% had organ-confined disease, extraprostatic extension, seminal vesicle involvement, or lymph node involvement, respectively. NOMOGRAMS Tables I to IV demonstrate the probability of presenting with the various pathologic stages when the preoperative serum, biopsy Gleason histologic grade, and clinical stage (AJCC 1992) are known. The updated nomograms have modified groups and Gleason sum groups. The groups are divided into five categories: 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10, and more than 10.0 ng/ml to further substratify men with respect to their level. Additionally, we substratified the Gleason scores into modified groups based on the risk of recurrence. In previous work from our institution, Kaplan-Meier actuarial survival curves (data not shown) for men with follow-up of more than 8 years demonstrated that biochemical progression-free survival for tumors with Gleason score 2 to 4 were similar, as were those with a within-the-groups Gleason score of 5 to 6 and 8 to Thus, these Gleason scores were subgrouped as 2 to 4, 5 to 6, or 8 to 10. Likewise, previous data have also demonstrated that Gleason sums of and behave differently and warrant substratification. 8 Like our previous nomograms,, Gleason score (biopsy), and clinical stage contributed significantly to the prediction of pathologic stage in the multinomial log-linear progression (P 0.001). Also, as seen in our previous nomograms, similar results were seen when was used as a continuous variable and all two-way and three-way interactions were tested and added little to the statistical significance of the final model (P 0.05). The final model contained only the main effects, and the combination of the three variables predicted better than any single variable. The medians (95% confidence intervals [CIs]) of the predicted probabilities from the multinomial log-linear regression analysis of 1000 bootstrap samples from the original study group are presented in the nomograms (Tables I to IV). The numbers within each cell of the nomogram represent the percentage of likelihood of a given pathologic stage based on the regression of all three variables combined. For example, a man with a preoperative serum level of 2.7 ng/ml and a biopsy Gleason score of 844 UROLOGY 58 (6), 2001

3 TABLE I. Clinical Stage T1c (nonpalpable, elevated) Organ confined 95 (89 99) 90 (88 93) 79 (74 85) 71 (62 79) 66 (54 76) Extraprostatic extension 5 (1 11) 9 (7 12) 17 (13 23) 25 (18 34) 28 (20 38) Seminal vesicle ( ) 0(0 1) 2 (1 5) 2 (1 5) 4 (1 10) Lymph node ( ) 1(0 2) 1 (0 4) 1 (0 4) Organ confined 92 (82 98) 84 (81 86) 68 (62 74) 58 (48 67) 52 (41 63) Extraprostatic extension 8 (2 18) 15 (13 18) 27 (22 33) 37 (29 46) 40 (31 50) Seminal vesicle ( ) 1(0 1) 4 (2 7) 4 (1 7) 6 (3 12) Lymph node ( ) 1(0 2) 1 (0 3) 1 (0 4) Organ confined 90 (78 98) 80 (78 83) 63 (58 68) 52 (43 60) 46 (36 56) Extraprostatic extension 10 (2 22) 19 (16 21) 32 (27 36) 42 (35 50) 45 (36 54) Seminal vesicle ( ) 1(0 1) 3 (2 5) 3 (1 6) 5 (3 9) Lymph node ( ) 0(0 1) 2 (1 3) 3 (1 5) 3 (1 6) Organ confined 87 (73 97) 75 (72 77) 54 (49 59) 43 (35 51) 37 (28 46) Extraprostatic extension 13 (3 27) 23 (21 25) 36 (32 40) 47 (40 54) 48 (39 57) Seminal vesicle ( ) 2(2 3) 8 (6 11) 8 (4 12) 13 (8 19) Lymph node ( ) 0(0 1) 2 (1 3) 2 (1 4) 3 (1 5) 10.0 Organ confined 80 (61 95) 62 (58 64) 37 (32 42) 27 (21 34) 22 (16 30) Extraprostatic extension 20 (5 39) 33 (30 36) 43 (38 48) 51 (44 59) 50 (42 59) Seminal vesicle ( ) 4(3 5) 12 (9 17) 11 (6 17) 17 (10 25) Lymph node ( ) 2(1 3) 8 (5 11) 10 (5 17) 11 (5 18) KEY: prostate-specific antigen. TABLE II. Clinical Stage T2a (palpable < 1 2 of one lobe) Organ confined 91 (79 98) 81 (77 85) 64 (56 71) 53 (43 63) 47 (35 59) Extraprostatic extension 9 (2 21) 17 (13 21) 29 (23 36) 40 (30 49) 42 (32 53) Seminal vesicle ( ) 1(0 2) 5 (1 9) 4 (1 9) 7 (2 16) Lymph node ( ) 0(0 1) 2 (0 5) 3 (0 8) 3 (0 9) Organ confined 85 (69 96) 71 (66 75) 50 (43 57) 39 (30 48) 33 (24 44) Extraprostatic extension 15 (4 31) 27 (23 31) 41 (35 48) 52 (43 61) 53 (44 63) Seminal vesicle ( ) 2(1 3) 7 (3 12) 6 (2 12) 10 (4 18) Lymph node ( ) 0(0 1) 2 (0 4) 2 (0 6) 3 (0 8) Organ confined 81 (63 95) 66 (62 70) 44 (39 50) 33 (25 41) 28 (20 37) Extraprostatic extension 19 (5 37) 32 (28 36) 46 (40 52) 56 (48 64) 58 (49 66) Seminal vesicle ( ) 1(1 2) 5 (3 8) 5 (2 8) 8 (4 13) Lymph node ( ) 1(0 2) 4 (2 7) 6 (3 11) 6 (2 12) Organ confined 76 (56 94) 58 (54 61) 35 (30 40) 25 (19 32) 21 (15 28) Extraprostatic extension 24 (6 44) 37 (34 41) 49 (43 54) 58 (51 66) 57 (48 65) Seminal vesicle ( ) 4(3 5) 13 (9 18) 11 (6 17) 17 (11 26) Lymph node ( ) 1(0 2) 3 (2 6) 5 (2 8) 5 (2 10) 10.0 Organ confined 65 (43 89) 42 (38 46) 20 (17 24) 14 (10 18) 11 (7 15) Extraprostatic extension 35 (11 57) 47 (43 52) 49 (43 55) 55 (46 64) 52 (41 62) Seminal vesicle ( ) 6(4 8) 16 (11 22) 13 (7 20) 19 (12 29) Lymph node ( ) 4(3 7) 14 (9 21) 18 (10 27) 17 (9 29) KEY: prostate-specific antigen and a nonpalpable (Stage T1c) digital rectal examination has an 84% probability of organ-confined disease. A man with a of 11.4 ng/ml and a biopsy Gleason score of 8 with a large palpable tumor (Stage T2c) has only a 6% chance of organ-confined disease at surgery. COMMENT The presentation of men with localized prostate cancer during the past 10 to 20 years has changed greatly. More men are presenting with well to moderately differentiated tumors (Gleason 4 to 6), UROLOGY 58 (6),

4 TABLE III. Clinical Stage T2b (palpable > 1 2 of one lobe, not on both lobes) Organ confined 88 (73 97) 75 (69 81) 54 (46 63) 43 (33 54) 37 (26 49) Extraprostatic extension 12 (3 27) 22 (17 28) 35 (28 43) 45 (35 56) 46 (35 58) Seminal vesicle ( ) 2(0 3) 6 (2 12) 5 (1 11) 9 (2 20) Lymph node ( ) 1(0 2) 4 (0 10) 6 (0 14) 6 (0 16) Organ confined 80 (61 95) 63 (57 69) 41 (33 48) 30 (22 39) 25 (17 34) Extraprostatic extension 20 (5 39) 34 (28 40) 47 (40 55) 57 (47 67) 57 (46 68) Seminal vesicle ( ) 2(1 4) 9 (4 15) 7 (3 14) 12 (5 22) Lymph node ( ) 1(0 2) 3 (0 8) 4 (0 12) 5 (0 14) Organ confined 75 (55 93) 57 (52 63) 35 (29 40) 25 (18 32) 21 (14 29) Extraprostatic extension 25 (7 45) 39 (33 44) 51 (44 57) 60 (50 68) 59 (49 69) Seminal vesicle ( ) 2(1 3) 7 (4 11) 5 (3 9) 9 (4 16) Lymph node ( ) 2(1 3) 7 (4 13) 10 (5 18) 10 (4 20) Organ confined 69 (47 91) 49 (43 54) 26 (22 31) 19 (14 25) 15 (10 21) Extraprostatic extension 31 (9 53) 44 (39 49) 52 (46 58) 60 (52 68) 57 (48 67) Seminal vesicle ( ) 5(3 8) 16 (10 22) 13 (7 20) 19 (11 29) Lymph node ( ) 2(1 3) 6 (4 10) 8 (5 14) 8 (4 16) 10.0 Organ confined 57 (35 86) 33 (28 38) 14 (11 17) 9 (6 13) 7 (4 10) Extraprostatic extension 43 (14 65) 52 (46 56) 47 (40 53) 50 (40 60) 46 (36 59) Seminal vesicle ( ) 8(5 11) 17 (12 24) 13 (8 21) 19 (12 29) Lymph node ( ) 8(5 12) 22 (15 30) 27 (16 39) 27 (14 40) KEY: prostate-specific antigen. TABLE IV. Clinical Stage T2c (palpable on both lobes) Organ confined 86 (71 97) 73 (63 81) 51 (38 63) 39 (26 54) 34 (21 48) Extraprostatic extension 14 (3 29) 24 (17 33) 36 (26 48) 45 (32 59) 47 (33 61) Seminal vesicle ( ) 1(0 4) 5 (1 13) 5 (1 12) 8 (2 19) Lymph node ( ) 1(0 4) 6 (0 18) 9 (0 26) 10 (0 27) Organ confined 78 (58 94) 61 (50 70) 38 (27 50) 27 (18 40) 23 (14 34) Extraprostatic extension 22 (6 42) 36 (27 45) 48 (37 59) 57 (44 70) 57 (44 70) Seminal vesicle ( ) 2(1 5) 8 (2 17) 6 (2 16) 10 (3 22) Lymph node ( ) 1(0 4) 5 (0 15) 7 (0 21) 8 (0 22) Organ confined 73 (52 93) 55 (44 64) 31 (23 41) 21 (14 31) 18 (11 28) Extraprostatic extension 27 (7 48) 40 (32 50) 50 (40 60) 57 (43 68) 57 (43 70) Seminal vesicle ( ) 2(1 4) 6 (2 11) 4 (1 10) 7 (2 15) Lymph node ( ) 3(1 7) 12 (5 23) 16 (6 32) 16 (6 33) Organ confined 67 (45 91) 46 (36 56) 24 (17 32) 16 (10 24) 13 (8 20) Extraprostatic extension 33 (9 55) 46 (37 55) 52 (42 61) 58 (46 69) 56 (43 69) Seminal vesicle ( ) 5(2 9) 13 (6 23) 11 (4 21) 16 (6 29) Lymph node ( ) 3(1 6) 10 (5 18) 13 (6 25) 13 (5 26) 10.0 Organ confined 54 (32 85) 30 (21 38) 11 (7 17) 7 (4 12) 6 (3 10) Extraprostatic extension 46 (15 68) 51 (42 60) 42 (30 55) 43 (29 59) 41 (27 57) Seminal vesicle ( ) 6(2 12) 13 (6 24) 10 (3 20) 15 (5 28) Lymph node ( ) 13 (6 22) 33 (18 49) 38 (20 58) 38 (20 59) KEY: prostate-specific antigen. levels less than 10.0 ng/ml, and nonpalpable (Stage T1c) disease. This dramatic change in presentation, which may be due to and better screening strategies, has nonetheless caused a major stage migration for prostate cancer, with nearly 60% of newly diagnosed cases presenting with localized or regional disease. 1 Our methods for predicting the pathologic stage, which were primarily developed from data collected from men treated before this stage migration, 2 4 must also evolve to allow us to make accurate predictions for men newly diagnosed with prostate cancer. For this reason, we have updated our nomograms ( Partin Tables ) to better represent the demographic, clini- 846 UROLOGY 58 (6), 2001

5 cal, and biochemical data of men presenting with prostate cancer in Like our previous tables, simple, easily obtainable variables were used (serum, biopsy Gleason score, and clinical stage [AJCC TNM-1992]) and combined into simple-touse tables. Several patients and physicians who used the previous nomograms 2 suggested that an individual with a serum level of 4.1 ng/ml must have a higher probability of organ-confined disease than an individual with a of 10.1 ng/ml with the same stage and Gleason score (eg, T2c and 3 4 7). Intuitively, this seemed obvious; however, the previous tables lumped these men into the same group and provided limited differentiation with respect to the likelihood of the various pathologic stages. In the previous (1997) nomograms, both men would have had a likelihood of organ-confined disease of 25%; the new (2001) nomograms provide the first man with a likelihood of organconfined disease of 31% (95% CI 23% to 41%). The second would have only an 11% (95% CI 7% to 17%) chance of organ-confined disease and no overlap in the confidence intervals. Additionally, two men with similar levels (eg, 5.2 ng/ml) and similar digital rectal examination results (eg, T2a) might have a biopsy Gleason score of (44% chance of organ-confined disease, 95% CI 39% to 50%) compared with a man with a biopsy Gleason score of who has only a 33% chance of organ-confined disease, 95% CI 25% to 41% (little overlap in confidence intervals). The further stratification of the Gleason groups and the groups are provided to better capture the actual probabilities of the various pathologic stages for the individual patient. Since we presented our 1997 updated nomograms, investigators at the Mayo Clinic have independently evaluated this method of stage prediction on their cohort of patients and provided excellent validation of this method. 9 Others have suggested the incorporation of race, 10 biopsy information such as the number of cores or the percentage of cores involved, 11 or use of transrectal ultrasound staging, 12 or nuclear chromatin texture characteristics 13 into similar staging models. Although these suggestions may improve the prediction of the pathologic stage, they make the use of simple tables more cumbersome because of the increased number of variables and have yet to be validated in large cohorts of patients. Large numbers of variables (greater than three or four) will require the use of neural networks for stage prediction and are presently being evaluated for this purpose. 14 Additionally, within this contemporary cohort, the numbers of biopsies with Gleason scores 2 to 4 are very limited and the probabilities should be interpreted with caution. At our institution, a Gleason score of 2 to 4 on prostate biopsy is no longer given. 15 With only 6% African-American men in this cohort, the utility of these tables for African-American men is questionable. Within the only subgroup of African-American men with enough numbers for statistical analysis (T1c, 3 3 6, 6.0 to 10.0 ng/ml, n 38), the rate of organ-confined cancer was 81% for all men, 81% for white men, and 80% for African-American men. Thus, we continue to caution use of these tables for African-American men until they can be validated in other cohorts with larger numbers of African- American men. The primary value of these updated Partin Tables will be for counseling patients regarding the probability of their tumor being a specific pathologic stage, rather than a strict decision-making tool. The nomograms may help patients and their treating physicians make informed decisions based on the probability of a pathologic stage, the individual patient s risk tolerance, and the values they place on the various potential outcomes. In addition, the use of these nomograms may aid in the rational selection of patients to undergo definitive therapy for prostate cancer with the hope of further improving the numbers and percentage of cancers that receive effective therapy that will cure the disease. CONCLUSIONS We have updated our nomograms for predicting pathologic stage for prostate cancer with a more contemporary cohort of men treated between 1994 and The new nomograms combine, biopsy Gleason score, and clinical stage with improved substratification of both Gleason and groups. 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