- A pathologist discusses factors that can help predict prostate cancer pathologic stage before surgery, including PSA levels, Gleason score on biopsy, percentage of biopsy cores involved with cancer, and clinical stage. Nomograms using these factors can estimate likelihood of organ-confined disease or extracapsular extension. - Repeat biopsy may help identify patients initially classified as low risk who actually have higher risk disease. Those with upgraded disease on repeat biopsy tended to have higher grade and stage cancers identified during prostatectomy. - Transition zone cancers may be missed on standard biopsy but detected with targeted biopsies of this area. Identifying these tumors preoperatively is important for predicting pathologic features.

1. PROSTATE CANCER:PREDICTING PATHOLOGIC STAGE Victor E. Reuter, M.D. Memorial Sloan-Kettering Cancer Center 2nd Interdisciplinary Conference on Prostate Cancer New York, April 2011

3. New and controversial issues

4. The role of repeat biopsy in selecting patients for further management

5. Prostate cancer in the context of zonal anatomy

7. Transrectal ultrasound (TRUS)

8. Magnetic Resonance Imaging/Spectroscopy

9. Serum prostatic specific antigen (PSA)

11. Shifts in pathological diagnosis and grading N = 1,148 (TURP and NBx) 20 15 10 Proportion of cohort 5 0 2 4 6 8 10 Gleason score at diagnosis Berney D et al, BJU Int 2007;100:1240

12. Reviewed Pathology - Gleason Score distribution: N = 1,724 40 30 20 Proportion of cohort 10 0 4 6 8 10 Reviewed Gleason score 133 patients (7%) were reassigned a nonmalignant diagnosis

14. Revised GS was associated with DSS (HR=1.71), p=0.001Berney D et al, BJU Int 2007;100:1240

16. Gleason 6 (3+3) 1 core / 14 cores Tot. Ca. Length 0.2 mm Tot. Core Length 136 mm % Cancer 0.15 % % G4/5 0 % Lat Lat Med Med NEG HG PIN NEG NEG Base Base Base TZ TZ NEG NEG NEG NEG NEG G6 (3+3) 1.6 % Mid Mid Mid ASAP NEG ASAP NEG Apex Apex Apex Rt. Lt.

17. Gleason 7 (3+4) 4 core / 14 cores Tot. Ca. Length 17.3 mm Tot. Core Length 130 mm % Cancer 13.3 % % G4/5 8.4 % Lat Lat Med Med G7 (3+4) 40% G7 (3+4 30% NEG G6 (3+3) 20% Base Base Base TZ TZ NEG NEG NEG NEG NEG G6 (3+3) 15 % Mid Mid Mid NEG NEG NEG NEG Apex Apex Apex Rt. Lt.

18. Variables Individually Correlated with Pathologic Stage Variablep value Biopsy Gleason score <0.0001 No. of involved cores <0.0001 Total percent of cancer <0.0001 Total millimeters of cancer <0.0001 Maximum millimeter of cancer on one core 0.0001 Serum PSA density 0.001 Maximum percent of cancer on one core 0.01 Bilateral cancer 0.01 Serum PSA value 0.028 Epstein. Urol 1998; 51:759-764.

19. Contemporary Preoperative Nomogram

20. Gleason 7 (4+3) pT2c (02’AJCC) ECE negative SVI negative LNI negative SM negative TTV 3.02 cm3 %G4/5 55 % MaxCaDiam 2.90 cm Prostate V 33.30 cm3 TTV/Prostate V 9.06 % Significant Gleason 6 (3+3) pT2c (02’AJCC) ECE none SVI negative LNI negative SM negative TTV 0.24 cm3 %G4/5 0 % MaxCaDiam 0.71 cm Prostate V 35.24 cm3 TTV/Prostate V 0.67 % Indolent Gl. 3 Gl. 4

21. Predicting the presence of an “indolent” cancer from clinical factors and systematic biopsy resultsEstimation of accuracy by ROC analysis 1.00 B 0.75 A Sensitivity 0.50 0.25 AUC A. PSA, cT stg, biopsy grade 0.781 B. A + PSAD, mm Ca, %Bx+0.881 0.00 0.00 0.25 0.50 0.75 1.00 1 - Specificity Ohori, Kattan et al, MSKCC, 2001

22. Nomogram to Predict an Indolent Cancer:<0.5 cc, confined, no Gleason patterns 4 or 5

23. Clinical and Biopsy Factors Associated with the Frequency of “Indolent” Cancer

24. PATHOLOGICAL FEATURES OF THE INITIAL AND REPEAT BIOPSIES Biopsy # of cores # of Pos. cores Length of Cores Length of Cancer Session mean mean mean (mm) mean (mm) Initial Bx. 8.33 2.0 71.2 7.14 n=59 (3-17) (1-7) (16-140) (0.5-55) Repeat Bx. 11.05 3.03 95.7 11.3 n=59* (7-19) (0-13)* (33.5-192) (0-67)* p-value .0001 .0107 .0001 .046 * 14 pts. had no cancer on repeat biopsy Sircar K, et al

25. CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY Repeat biopsy Pre-operative PSA % Free PSA Prostate Volume PSA density ng/ml, median median cm3, median ng/ml/cm3, median Negative 3.725 18 34.05 0.083 n=14 (1.38-13.8) (5-31.8) (15.5-204.5) (.05-.241) Positive 6.605 11 37.15 0.191 n=45 (.29-27.91) (2.5-71.5) (12.6-78.27) (.007-.754) p-value 0.0279 0.0126 0.7992 0.0476 Sircar K, et al

26. CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY Repeat biopsy % cancer in % positive cores Gleason 4/5 in Previous negative first + biopsy in first + biopsy first + biopsy biopsy sessions(%) Negative 1.86 11.8 0 11 (79) (n=14) (0.4-6.1) (8.33-16.6) Positive 7.69 25 20 (44%) 2 (5) (n=45) (1.05-86.6) (9.1-100) p-value 0.0089 0.0017 0.002 <.0005 Sircar K, et al

27. PATHOLOGIC FEATURES OF CANCER IN RADICAL PROSTATECTOMY SPECIMENS BASED THE RESULT OF THE REPEAT BIOPSY Pathologic Stage (%) Repeat Indolent Tumor Volume % Gleason 4/5 Confined ECE SVI LN mets Biopsy cancer cm3 cancer pT2 pT3a pT3b pN+ Negative 10 .202 0 14 0 0 0 n=14 (71%) (.016-4.53) (100%) Positive 3 2.52 4.96 29 12* 4 0 n=45 (7%) (.145-23.84) (0-100%) (67) (27) (4) p-value <.0005 <.0005 .0031 .0012 .017 .417 -- * 8 pts. had established ECE Subsequent study (Berglund RK et al J Urol 2008;180:1964) on 104 eligible patients**: - Repeat Bx negative in 26%. - 27% cases upgraded or upstaged - Upgraded/upstaged cases were associated with higher grade (0.001) and pT (0.003) at RRP.

28. REPEAT BIOPSY FINDINGS IN A COHORT OF PATIENTS UNDERGOING PROSTATECTOMY Among 3296 patients who had radical prostatectomy between 2000-2005, 285 (9%) had both a positive > 12 core NB and RP 51/285 patients with low risk pathologic features on first diagnostic biopsy and who subsequently underwent early repeat NB and radical prostatectomy 46 patients remain in cohort: Clinical stage: 37 cT1c, 9 cT2a PSA: mean 5.3, median 4.7 Time between NB: mean 4.9 mos, median 3.3 mos # of cores in initial biopsy: mean 10.9, median 12 Fine SW et al, USCAP 2010

29. Results – Repeat NB Group 1 [n=10; 22%]: still had low risk features All GS 3+3=6 # cores positive: one (7/10), two (3/10) % core involvement: 1-20% At prostatectomy: all cases organ-confined Group 2 [n=36; 78%]: exceeded low risk features Exceeded one criterion: 15 patients Exceeded two criteria: 13 patients Exceeded three criteria: 8 patients At prostatectomy: pT2 = 27 (75%), pT2+ = 3 (8%), pT3a = 6 (17%), and large anterior tumors Fine SW et al, USCAP 2010

31. TRANSITION ZONE-DIRECTED BIOPSY: DETECTION OF TZ CANCER 61 cases with TZ-directed NB-detected cancer and corresponding RP Prostate cancer was detected in: Left TZ-directed Nbx: 25/61 (41%) Right TZ-directed Nbx: 23/61 (38%) Bilateral TZ-directed Nbx: 13/61 (21%) On RP: 24/61 (39.5%) cases had no tumor in the TZ 24/61 (39.5%) cases showed non-dominant TZ cancer 13/61 (21%) displayed a dominant TZ lesion Haarer C, et al J Urol 2009:182:1340

32. Preoperative Prediction of Pathologic Stage: Summary of Multivariate Analysis Findings in 349 Cases Outcome VariablePreoperative Variablep Extraprostatic extension (yes/no) PSA 0.0001 % of biopsy involved 0.0001 Gleason score 0.0103 Clinical stage 0.1853 NS Perineural invasion 0.8178 NS Seminal vesicle invasion % of biopsy involved 0.0006 PSA 0.0033 Gleason score 0.0108 Clinical stage 0.2893 NS Perineural invasion 0.9797 NS Pathologic stage PSA 0.0001 % of biopsy involved 0.0001 Gleason score 0.0003 Clinical stage 0.2107 NS Perineural invasion 0.4189 NS Egan et al. 1997; 21:1496-1500

33. PERINEURAL INVASION Morphologic criteria are important Importance in predicting extracapsular extension (NB) or biochemical recurrence is controversial Am J Surg Pathol. 1993;17:336 J Urol. 1999;162:103 Importance of the diameter of the nerve involved in predicting failure has not been confirmed Unanswered questions on NBx: amount, location, size

34. INTRADUCTALCARCINOMA Cohen et al, Arch Pathol Lab Med 2007;131

36. High tumor volume

37. Extracapsular extension (pT3)

38. Disease progressionGuo et al Mod Pathol 2006;19:1528 Robinson BD , et al J Urol 2010;184:1328

40. Ki67: BJ Cancer 2009;100:888 (and others)

41. Myc: Mod Pathol 2002;15:35

43. Gene signature (Myriad): Lancet Oncol 2011;11:245p = 0.01 p = 0.86 Postoperative Model Gene Expression Model Combined Model Stephenson AJ et al. Cancer 2005;104:290