Basic & translational oncology MolMed, Rotterdam Oct 9, 2018 What every scientist should know about pathology: lessons from the prostate Arno van Leenders Pathology Erasmus MC, Rotterdam
The Prostate 1 cm
The Prostate 1. Description 2. Ink margins 3. Freeze for research
90% 60% Frozen and FFPE samples 5% are very heterogeneous
Pathological assessment • Gleason score • pT-stage (extra-prostatic growth) • Surgical margin • Lymph node metastasis
Gleason grading system 1966 - 2016: 50 th anniversary Based on tumor growth patterns Accounts for tumor heterogeneity Modifications in 2005 and 2016
Normal Gleason 3
Gleason 4 Gleason 5
Gleason score Accounts for heterogeneity: adding 2 most common patterns Gleason 3 Gleason 4 Gleason score: 3 + 4 = 7
Gleason score 6 does not cause PCa death 3+3=6 3+4=7 4+3=7 >7 n = 1101
Gleason score 3+4=7 on biopsy “The 2 most common patterns ” G3 55% G4 45% Gleason score 3+4=7 G3 99% G4 1%
Quantification of Grade 4 component BCRFS after radical prostatectomy G4 % in GS 7 6 6 5% 7 (3+4) 6-10% 7 (3+4) 11-20% 7 (3+4) 21-30% 7 (4+3) 31-49% 8 7 (4+3) 50-60% 9-10 61-80% 7 (4+3) 8 >80% 9-10 Sauter Eur Urol 2016
GG 5 κ fused GG 4 ill-formed κ glomeruloid GG 3 cribriform
Frequency Gleason grade 4 patterns Ill-defined 66% One pattern 22% Fused 76% Two patterns 47% Glomeruloid 28% Three patterns 26% Cribriform 38% Four patterns 5%
Cribriform GS 7 at radical prostatectomy without cribriform with cribriform
Cribriform GS 7 at biopsy
Cribriform GS 7 at biopsy
Cribriform GS 7 at biopsy: BCRFS
Cribriform growth and % GG4 are related Parameter Percentage Gleason grade 4 P-value 0-10% 10-25% 25-50% Number 121 131 118 Age 65 (66; 61-70) 67 (68; 63-72) 68 (69; 65-72) .001 PSA (ng/mL) 7.8 (5.2; 3.7-7.1) 9.2 (5.9; 4.2-9.0) 11.7 (8.5; 5.4-13.4) <.001 % positive biopsies 51 (50; 33-67) 44 (43; 29-57) 48 (43; 29-67) .01 % tumor volume 39 (37; 25-52) 44 (45; 27-59) 50 (51; 34-65) .001 CR/IDC 7 (6%) 29 (22%) 52 (44%) <.001 Disease-specific death 4 (3%) 6 (5%) 13 (11%) .02
Biomarkers for risk stratification Commercially available, standardized tests Commercial test Based Specimen Outcome Decipher 22 genes RP metastasis Oncotype DX 12 genes PBx, RP adverse PA at RP, BCR, metastasis Prolaris 31 genes PBx, RP BCR, DFS ProMark 8 genes PBx adverse PA at RP Validated in several studies Additive value to existing nomograms
Biomarker test versus pathology 2018? No information on % GG4 Invasive and intraductal carcinoma not considered Sampling artefact? Increased use of multiparametric MRI Additional value in contemporary cohorts to be determined
“Easy” biomarkers in prostate cancer Potential value for Ki67, p27, EZH2, c- MYC, PTEN, … Different antibodies, platforms, cut-offs, endpoints , … Subjective scoring “ eye balling” No additional value in prostate cancer stratification
Molecular biology of GS 3+4=7? HE DNA/RNA Growth patterns 3+4=7 3 4 cr 3 3 4 ill Genomic black box
Genomic instability in cribriform growth + + CR - - + - - - + GS 6 3+4 4+3 8 9-10 Chua, Eur Urol 2017; Böttcher, Submitted
GG4 cribriform: progressive genomic loss GG3 Cribriform GG4
Molecular background GG4 cribriform CISH c-MY C in 20 prostate cancer specimens 500 cells counted (amplification if mean > 2.2)
GG4 ill-defined: EMT/Cadherin switching N-Cadherin ill-defined GG4 Kolijn, Oncotarget 2015
Microscopic evolution … ? 1674 2016
Histopathologic delineation ? ? ? ? Gleason grade 3
x y 800 µ m z GG 4 ill-formed BABB clearing Before After
GG 3 glandular GG 4 ill-formed GG 4 cribriform
Take home messages Gain basic knowledge of pathology Far more to say, than PA report only Contact your pathologist at early stage
Thank you! Rotterdam, NL Chris Bangma Rene Böttcher Guido Jenster Charlotte Kweldam Daan Nieboer Monique Roobol Martin van Royen Ewout Steyerberg Esther Verhoef Toronto, CA Paul Boutros Rob Bristow Michael Fraser Theo van der Kwast g.vanleenders@erasmusmc.nl
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