PROSTATE CANCER:PREDICTING PATHOLOGIC STAGE<br />Victor E. Reuter, M.D.<br />Memorial Sloan-Kettering Cancer Center<br />2...
OUTLINE<br />A Pathologist’s perspective:<br /><ul><li> Preoperative factors associated with pathologic stage
 New and controversial issues
 The role of repeat biopsy in selecting patients for further management
 Prostate cancer in the context of zonal anatomy
 Notes on including markers to improve predictive models</li></li></ul><li>PROSTATIC ADENOCARCINOMARoutine Diagnostic/Prog...
Transrectal ultrasound (TRUS)
Magnetic Resonance Imaging/Spectroscopy
Serum prostatic specific antigen (PSA)
Pathology</li></ul>	- transrectal biopsy / TURP<br />	- prostatectomy<br /><ul><li>Markers</li></li></ul><li>NOMOGRAM FOR ...
Shifts in pathological diagnosis and grading N = 1,148 (TURP and NBx)<br />20<br />15<br />10<br />Proportion of cohort<br...
Reviewed Pathology - Gleason Score distribution: N = 1,724<br />40<br />30<br />20<br />Proportion of cohort<br />10<br />...
DSS: Reviewed Gleason score<br />Multivariate analysis (adjusted for clinical stage, PSA, specimen type):<br /><ul><li> Or...
 Revised GS was associated with DSS (HR=1.71), p=0.001</li></ul>Berney D et al, BJU Int 2007;100:1240<br />
 0<br />10<br />20<br />30<br />40<br />50<br />60<br />70<br /> 80<br />90<br />100<br />Preoperative Nomogram for Prosta...
Gleason 6 (3+3)<br />1 core / 14 cores<br />Tot. Ca. Length	 0.2 mm<br />Tot. Core Length	136 mm<br />% Cancer	     	0.15 ...
Gleason 7 (3+4)<br />4 core / 14 cores<br />Tot. Ca. Length	 17.3 mm<br />Tot. Core Length	130 mm<br />% Cancer	     	13.3...
Variables Individually Correlated with Pathologic Stage<br />Variablep value<br />Biopsy Gleason score	<0.0001<br />	No. o...
Contemporary Preoperative Nomogram<br />
Gleason 7 (4+3)   <br />pT2c (02’AJCC)<br />ECE	negative<br />SVI	negative<br />LNI	negative<br />SM	negative<br />TTV		3....
Predicting the presence of an “indolent” cancer<br />from clinical factors and systematic biopsy resultsEstimation of accu...
Nomogram to Predict an Indolent Cancer:<0.5 cc, confined, no Gleason patterns 4 or 5<br />
Clinical and Biopsy Factors <br />Associated with the Frequency of “Indolent” Cancer<br />
PATHOLOGICAL FEATURES OF THE INITIAL AND REPEAT BIOPSIES <br />Biopsy	     # of cores	# of Pos. cores	Length of Cores	Leng...
CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY<br />Repeat biopsy	Pre-operative PSA	  % ...
CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY<br />Repeat biopsy	 % cancer in	% positiv...
PATHOLOGIC FEATURES OF CANCER IN RADICAL PROSTATECTOMY SPECIMENS BASED THE RESULT OF THE REPEAT BIOPSY<br />							Patholo...
REPEAT BIOPSY FINDINGS IN A COHORT OF PATIENTS UNDERGOING PROSTATECTOMY<br />Among 3296 patients who had radical prostatec...
Results – Repeat NB<br />Group 1 [n=10; 22%]: still had low risk features<br /> All GS 3+3=6<br /> # cores positive: one (...
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NY Prostate Cancer Conference - V.E. Reuter - Session 2: Upgrading/downgrading of prostate cancer from biopsy to radical prostatectomy: Incidence and predictive factors

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NY Prostate Cancer Conference - V.E. Reuter - Session 2: Upgrading/downgrading of prostate cancer from biopsy to radical prostatectomy: Incidence and predictive factors

  1. 1. PROSTATE CANCER:PREDICTING PATHOLOGIC STAGE<br />Victor E. Reuter, M.D.<br />Memorial Sloan-Kettering Cancer Center<br />2nd Interdisciplinary Conference on Prostate Cancer<br />New York, April 2011<br />
  2. 2. OUTLINE<br />A Pathologist’s perspective:<br /><ul><li> Preoperative factors associated with pathologic stage
  3. 3. New and controversial issues
  4. 4. The role of repeat biopsy in selecting patients for further management
  5. 5. Prostate cancer in the context of zonal anatomy
  6. 6. Notes on including markers to improve predictive models</li></li></ul><li>PROSTATIC ADENOCARCINOMARoutine Diagnostic/Prognostic Armament<br /><ul><li>Digital rectal examination (DRE)
  7. 7. Transrectal ultrasound (TRUS)
  8. 8. Magnetic Resonance Imaging/Spectroscopy
  9. 9. Serum prostatic specific antigen (PSA)
  10. 10. Pathology</li></ul> - transrectal biopsy / TURP<br /> - prostatectomy<br /><ul><li>Markers</li></li></ul><li>NOMOGRAM FOR PREDICTINGPATHOLOGIC STAGE<br />Johns Hopkins, Baylor, U. Michigan SPOREs<br />PSA 4.1-10 PSA 10.1-20<br />Gleason Sum Clinical Stage Clinical Stage<br />T1c T2b T3a T1c T2b T3a<br />Organ-Confined<br />5 69 38 23 57 28 16<br /> (63-74) (32-45) (13-38) (50-64) (22-34) (8-28)<br />7 48 21 11 36 14 7.2<br /> (42-53) (17-25) (5.8-20) (30-42) (11-18) (4-14)<br />Modified from Partin AW, Kattan MW, Subong ENP, Walsh PC, Wojno KJ, Oesterling JE, Scardino PT, Pearson JD. JAMA 1997; 277:1445.<br />
  11. 11. Shifts in pathological diagnosis and grading N = 1,148 (TURP and NBx)<br />20<br />15<br />10<br />Proportion of cohort<br />5<br />0<br />2<br />4<br />6<br />8<br />10<br />Gleason score at diagnosis<br />Berney D et al, BJU Int 2007;100:1240<br />
  12. 12. Reviewed Pathology - Gleason Score distribution: N = 1,724<br />40<br />30<br />20<br />Proportion of cohort<br />10<br />0<br />4<br />6<br />8<br />10<br />Reviewed Gleason score<br />133 patients (7%) were reassigned a nonmalignant diagnosis<br />
  13. 13. DSS: Reviewed Gleason score<br />Multivariate analysis (adjusted for clinical stage, PSA, specimen type):<br /><ul><li> Original GS was not associated with DSS (HR=1.03), p=0.65
  14. 14. Revised GS was associated with DSS (HR=1.71), p=0.001</li></ul>Berney D et al, BJU Int 2007;100:1240<br />
  15. 15. 0<br />10<br />20<br />30<br />40<br />50<br />60<br />70<br /> 80<br />90<br />100<br />Preoperative Nomogram for Prostate Cancer Recurrence<br />Points<br />PSA<br />4<br />20<br />0.1<br />1<br />2<br />3<br />6<br />8<br />9<br />10<br />12<br />16<br />30<br />45<br />70<br />110<br />7<br />T2a<br />T2c<br />T3a<br />ClinicalStage<br />T1c<br />T1ab<br />T2b<br /> 2+3<br />3+  2<br /> 4+4<br />Biopsy Gleason Grade<br /> 2+  2<br />3+3<br /> 3+ 4<br />Total Points<br /> 0<br />20<br />40<br />60<br />80<br />100<br />120<br />140<br />160<br />180<br />200<br />60MonthRec. Free Prob.<br />.96<br />.93<br />.9<br />.85<br />.8<br />.7<br />.6<br />.5<br />.4<br />.3<br />.2<br />.1<br />.05<br />Instructions for Physician: Locate the patient’s PSA on the PSA axis. Draw a line straight upwards to the Points axis to determine how many points towards recurrence the patient receives for his PSA. Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time drawing straight upward to the Points axis. Sum the points achieved for each predictor and locate this sum on the Total Points axis. Draw a line straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first.<br />Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy. You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer.<br />Instruction to Patient: “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”<br /><ul><li>1997 Michael W. Kattan and Peter T. Scardino</li></ul>Kattan MW et al: JNCI 1998; 90:766-771.<br />
  16. 16. Gleason 6 (3+3)<br />1 core / 14 cores<br />Tot. Ca. Length 0.2 mm<br />Tot. Core Length 136 mm<br />% Cancer 0.15 %<br />% G4/5 0 %<br />Lat<br />Lat<br />Med<br />Med<br />NEG<br />HG PIN<br />NEG<br />NEG<br />Base<br />Base<br />Base<br />TZ<br />TZ<br />NEG<br />NEG<br />NEG<br />NEG<br />NEG<br />G6 (3+3)<br />1.6 %<br />Mid<br />Mid<br />Mid<br />ASAP<br />NEG<br />ASAP<br />NEG<br />Apex<br />Apex<br />Apex<br />Rt.<br />Lt.<br />
  17. 17. Gleason 7 (3+4)<br />4 core / 14 cores<br />Tot. Ca. Length 17.3 mm<br />Tot. Core Length 130 mm<br />% Cancer 13.3 %<br />% G4/5 8.4 %<br />Lat<br />Lat<br />Med<br />Med<br />G7 (3+4)<br />40%<br />G7 (3+4<br />30%<br />NEG<br />G6 (3+3)<br />20%<br />Base<br />Base<br />Base<br />TZ<br />TZ<br />NEG<br />NEG<br />NEG<br />NEG<br />NEG<br />G6 (3+3)<br />15 %<br />Mid<br />Mid<br />Mid<br />NEG<br />NEG<br />NEG<br />NEG<br />Apex<br />Apex<br />Apex<br />Rt.<br />Lt.<br />
  18. 18. Variables Individually Correlated with Pathologic Stage<br />Variablep value<br />Biopsy Gleason score <0.0001<br /> No. of involved cores <0.0001<br /> Total percent of cancer <0.0001<br /> Total millimeters of cancer <0.0001<br /> Maximum millimeter of cancer on one core 0.0001<br /> Serum PSA density 0.001<br /> Maximum percent of cancer on one core 0.01<br /> Bilateral cancer 0.01<br /> Serum PSA value 0.028<br />Epstein. Urol 1998; 51:759-764.<br />
  19. 19. Contemporary Preoperative Nomogram<br />
  20. 20. Gleason 7 (4+3) <br />pT2c (02’AJCC)<br />ECE negative<br />SVI negative<br />LNI negative<br />SM negative<br />TTV 3.02 cm3<br />%G4/5 55 %<br />MaxCaDiam 2.90 cm<br />Prostate V 33.30 cm3<br />TTV/Prostate V 9.06 %<br />Significant<br />Gleason 6 (3+3) <br />pT2c (02’AJCC)<br />ECE none <br />SVI negative<br />LNI negative<br />SM negative<br />TTV 0.24 cm3<br />%G4/5 0 %<br />MaxCaDiam 0.71 cm<br />Prostate V 35.24 cm3<br />TTV/Prostate V 0.67 %<br />Indolent<br />Gl. 3<br />Gl. 4<br />
  21. 21. Predicting the presence of an “indolent” cancer<br />from clinical factors and systematic biopsy resultsEstimation of accuracy by ROC analysis<br />1.00<br />B<br />0.75<br />A<br />Sensitivity<br />0.50<br />0.25<br />AUC<br />A. PSA, cT stg, biopsy grade 0.781<br />B. A + PSAD, mm Ca, %Bx+0.881<br />0.00<br />0.00<br />0.25<br />0.50<br />0.75<br />1.00<br />1 - Specificity<br />Ohori, Kattan et al, MSKCC, 2001<br />
  22. 22. Nomogram to Predict an Indolent Cancer:<0.5 cc, confined, no Gleason patterns 4 or 5<br />
  23. 23. Clinical and Biopsy Factors <br />Associated with the Frequency of “Indolent” Cancer<br />
  24. 24. PATHOLOGICAL FEATURES OF THE INITIAL AND REPEAT BIOPSIES <br />Biopsy # of cores # of Pos. cores Length of Cores Length of Cancer<br />Session mean mean mean (mm) mean (mm)<br />Initial Bx. 8.33 2.0 71.2 7.14 <br /> n=59 (3-17) (1-7) (16-140) (0.5-55) <br />Repeat Bx. 11.05 3.03 95.7 11.3 <br /> n=59* (7-19) (0-13)* (33.5-192) (0-67)* <br />p-value .0001 .0107 .0001 .046 <br />* 14 pts. had no cancer on repeat biopsy <br />Sircar K, et al<br />
  25. 25. CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY<br />Repeat biopsy Pre-operative PSA % Free PSA Prostate Volume PSA density<br /> ng/ml, median median cm3, median ng/ml/cm3, median<br />Negative 3.725 18 34.05 0.083<br /> n=14 (1.38-13.8) (5-31.8) (15.5-204.5) (.05-.241)<br /> Positive 6.605 11 37.15 0.191<br /> n=45 (.29-27.91) (2.5-71.5) (12.6-78.27) (.007-.754)<br /> p-value 0.0279 0.0126 0.7992 0.0476 <br />Sircar K, et al<br />
  26. 26. CLINICAL AND BIOPSY FEATURES IN 59 PATIENTS ACCORDING TO RESULT OF REPEAT BIOPSY<br />Repeat biopsy % cancer in % positive cores Gleason 4/5 in Previous negative first + biopsy in first + biopsy first + biopsy biopsy sessions(%)<br />Negative 1.86 11.8 0 11 (79)<br /> (n=14) (0.4-6.1) (8.33-16.6)<br />Positive 7.69 25 20 (44%) 2 (5)<br /> (n=45) (1.05-86.6) (9.1-100)<br />p-value 0.0089 0.0017 0.002 <.0005 <br />Sircar K, et al<br />
  27. 27. PATHOLOGIC FEATURES OF CANCER IN RADICAL PROSTATECTOMY SPECIMENS BASED THE RESULT OF THE REPEAT BIOPSY<br /> Pathologic Stage (%)<br />Repeat Indolent Tumor Volume % Gleason 4/5 Confined ECE SVI LN mets <br />Biopsy cancer cm3 cancer pT2 pT3a pT3b pN+<br />Negative 10 .202 0 14 0 0 0<br /> n=14 (71%) (.016-4.53) (100%)<br />Positive 3 2.52 4.96 29 12* 4 0<br /> n=45 (7%) (.145-23.84) (0-100%) (67) (27) (4)<br />p-value <.0005 <.0005 .0031 .0012 .017 .417 --<br />* 8 pts. had established ECE<br />Subsequent study (Berglund RK et al J Urol 2008;180:1964) on 104 eligible patients**:<br />- Repeat Bx negative in 26%. - 27% cases upgraded or upstaged<br />- Upgraded/upstaged cases were associated with higher grade (0.001) and pT (0.003) at RRP.<br />
  28. 28. REPEAT BIOPSY FINDINGS IN A COHORT OF PATIENTS UNDERGOING PROSTATECTOMY<br />Among 3296 patients who had radical prostatectomy between 2000-2005, 285 (9%) had both a positive > 12 core NB and RP<br />51/285 patients with low risk pathologic features on first diagnostic biopsy and who subsequently underwent early repeat NB and radical prostatectomy<br />46 patients remain in cohort:<br />Clinical stage: 37 cT1c, 9 cT2a<br /> PSA: mean 5.3, median 4.7<br /> Time between NB: mean 4.9 mos, median 3.3 mos<br /> # of cores in initial biopsy: mean 10.9, median 12<br />Fine SW et al, USCAP 2010<br />
  29. 29. Results – Repeat NB<br />Group 1 [n=10; 22%]: still had low risk features<br /> All GS 3+3=6<br /> # cores positive: one (7/10), two (3/10)<br /> % core involvement: 1-20%<br />At prostatectomy: all cases organ-confined<br />Group 2 [n=36; 78%]: exceeded low risk features<br /> Exceeded one criterion: 15 patients<br /> Exceeded two criteria: 13 patients<br /> Exceeded three criteria: 8 patients<br />At prostatectomy: pT2 = 27 (75%), pT2+ = 3 (8%), pT3a = 6 (17%), and large anterior tumors<br />Fine SW et al, USCAP 2010<br />
  30. 30. Anterior Dominant Tumors: Zone of Origin (n=197)<br /><ul><li>197 tumors</li></ul>Peripheral Zone: 97<br />Transition Zone: 70<br /> PZ+TZ: 14<br />IND: 16<br />Al-Ahmadie HA et al AJSP 2008;32:229<br />
  31. 31. TRANSITION ZONE-DIRECTED BIOPSY: DETECTION OF TZ CANCER<br /> 61 cases with TZ-directed NB-detected cancer and corresponding RP<br />Prostate cancer was detected in:<br />Left TZ-directed Nbx: 25/61 (41%)<br />Right TZ-directed Nbx: 23/61 (38%)<br />Bilateral TZ-directed Nbx: 13/61 (21%)<br />On RP:<br />24/61 (39.5%) cases had no tumor in the TZ<br />24/61 (39.5%) cases showed non-dominant TZ cancer<br />13/61 (21%) displayed a dominant TZ lesion<br />Haarer C, et al J Urol 2009:182:1340<br />
  32. 32. Preoperative Prediction of Pathologic Stage: Summary of Multivariate Analysis Findings in 349 Cases<br />Outcome VariablePreoperative Variablep<br />Extraprostatic extension (yes/no) PSA 0.0001<br /> % of biopsy involved 0.0001<br /> Gleason score 0.0103<br /> Clinical stage 0.1853 NS<br /> Perineural invasion 0.8178 NS<br />Seminal vesicle invasion % of biopsy involved 0.0006<br /> PSA 0.0033<br /> Gleason score 0.0108<br /> Clinical stage 0.2893 NS<br /> Perineural invasion 0.9797 NS<br />Pathologic stage PSA 0.0001<br /> % of biopsy involved 0.0001<br /> Gleason score 0.0003<br /> Clinical stage 0.2107 NS<br /> Perineural invasion 0.4189 NS<br />Egan et al. 1997; 21:1496-1500<br />
  33. 33. PERINEURAL INVASION<br />Morphologic criteria are important<br />Importance in predicting extracapsular extension (NB) or biochemical recurrence is controversial<br />Am J Surg Pathol. 1993;17:336<br />J Urol. 1999;162:103<br />Importance of the diameter of the nerve involved in predicting failure has not been confirmed <br />Unanswered questions on NBx: amount, location, size<br />
  34. 34. INTRADUCTALCARCINOMA<br />Cohen et al, Arch Pathol Lab Med 2007;131<br />
  35. 35. INTRADUCTAL CARCINOMA ON NEEDLE BIOPSY<br />Associations at prostatectomy:<br /><ul><li> High Gleason grade
  36. 36. High tumor volume
  37. 37. Extracapsular extension (pT3)
  38. 38. Disease progression</li></ul>Guo et al Mod Pathol 2006;19:1528<br />Robinson BD , et al J Urol 2010;184:1328<br />
  39. 39. HOW ABOUT TISSUE BASED MARKERS?<br /><ul><li> Ploidy: Anticancer Res 2011;30:719
  40. 40. Ki67: BJ Cancer 2009;100:888 (and others)
  41. 41. Myc: Mod Pathol 2002;15:35
  42. 42. Systems Path (Aureon): Cancer 2009;115:303</li></ul> J Urol 2009;182:125<br /><ul><li> CNA (MSK): Cancer Cell 2010;18:11
  43. 43. Gene signature (Myriad): Lancet Oncol 2011;11:245</li></ul>p = 0.01<br />p = 0.86<br />Postoperative Model<br />Gene Expression Model<br />Combined Model<br />Stephenson AJ et al. Cancer 2005;104:290<br />

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