Grading Prostate Cancer: Recent Changes and Refinements

USPSTF: 2012 Report on serum PSA Screening Recommendation rating of D Reduced screening, Reduced biopsies, reduced incidence Refinements currently occurring in 2017. WHY? Grading Prostate Cancer: Recent Changes and Refinements Current Issues in Pathology May 25, 2017 Eapen, et al., Curr. Op. Urol. 27(3): 205-9 ( May 2017) Jeffry P. Simko, PhD, MD Professor of Clinical Pathology Departments of Urology, Radiation Oncology and Anatomic Pathology Disclosures: GenomeDx: Consultant 3D Biopsy: Advisory Board, Consultant 3 Scan: Advisory Board, Consultant Motivation: Recent adjustments to Gleason Grading for prostatic adenocarcinoma 2005 & 2014 ISUP Gleason Consensus Meetings 2014 Proposal of Prognostic Grade Groups (Gleason Grade Groups or GGG) More than half dozen outcome studies. WHO ( Blue Book ) / CAP Endorsements Future needs & adjustments? Problem areas that still exist! Correlations with molecular patterns 3D pathology and image analysis 1

Grading Cancers of the Prostate: Prostatic adenocarcinoma (> 99%) Acinar type atrophic, foamy, pseudohyperplastic, others Ductal type Mucinous type Vacuolated type (signet ring cell-like) Grading Systems (more than 40): Architecture vs. Cytology vs. Combinations Other carcinoma and malignant tumor types (essentially all are high grade. Many Treatment-Related?) Urothelial carcinoma Squamous cell carcinoma Small cell carcinoma Adenosquamous carcinoma Metaplastic carcinoma / carcinosarcoma and sarcomas Urol Surg Pathol 1 st Ed. (Elsevier, Bostwick & Eble: 1996) Gleason Grading: The most important tissue-based prognostic and predictive factor (WHO Blue Book, 2016) Not accepted by WHO until 2003! Predicts stage, treatment outcomes, recurrence, progression and death! Original Gleason System Formulated 60 s, validated 70 s, continued valids. Architecture alone (not cytology) Tumor heterogeneity is taken into account Grades: 1-5 based on gland growth patterns Profound effects on Management Active surveillance ( No pattern 4? ) Type of radiation? + / - Anti-androgens Adjuvant therapy post prostatectomy? Grade X + Grade Y = Score ( sum: 2-10 ) X = Most common tumor growth pattern (primary grade) Y = Second most common pattern (Secondary grade) If Y < 5% (< 3%) of total tumor, then repeat X. For Primary tumor ( Not for treated tumor or METs. ) 2

DF Gleason, 1966 Gleason pattern 1: Circumscribed nodule of uniform glands Uniform glands with no fusion ( fusion is 4) Never call on Bx, only RP Extremely rare, usually other patterns too Gleason Pattern 2: Regular or irregular glands in a less circumscribed nodule. No intervening benign glands (that is 3) Individual glands, no fusion (fusion is 4) 3

Gleason pattern 3: Individual glands infiltrating benign Irregular distribution (not uniform) Regular distribution OK if B9 incorporated 4

DF Gleason, 1977 5

Gleason Pattern 4: Gland fusion Cribriform (glomerulations) Sinuating small glands in chains or cords Poorly formed glands? High grade tumor (changes Rx options) 6

Jesses comments. 7

Gleason Pattern 5: Single cells, solid sheets or necrosis in 4 Vacuoles are not pattern 4! McKenney, et al., Am J Surg Pathol 40: 1439 (2016) 9

More sclerotic. Dolphining McKenney, et al., Am J Surg Pathol 40: 1439 (2016) 11

Treated Carcinoma: Post radiation and/or anti-androgen Rx. Atrophic, associated inflammation, changes in the benign. ONLY grade if treatment changes not seen! Sometimes both treated & untreated (report). 12

Grading Variants: Use the Gleason growth pattern Variants and subtypes not well-defined. Classic examples, OK, BUT borders, continuum Acinar variants and subtypes. Outcome data supports this. 13

treated issues. 15

McKenney, et al., Am J Surg Pathol 40: 1439 (2016) Vacuoles all of them. 16

Gleason Modifications: ISUP International Society of Urologic Pathologists Consensus Meetings: 2005, 2014 Subtypes foamy, muycinous, pseudohyperplastic, atrophic. Dozens of prostate pathologists at the meetings Treating clinicians also attended the 2014 meeting Identify common areas: Consensus statements Identify areas of confusion: Experiments to clarify 2005 results criticized for no outcome data! Outcome studies have now validated virtually all Increased consistency in grading ( cribriform ) Problems with original Gleason (2005 & 2014 ISUP) Some patterns are extremely rare / not cancer? Grade 1 likely adenosis (Basal Cell IHC) Grade 2 Rare / Can t Dx on small needle Bx Not all possible growth patterns represented Inter-observer variability; degraded prognostics Some descriptions vague Cribriform 3 vs. Cribriform 4 Inter-observer variability; degraded prognostics No rules for when more than two patterns RARE 17

Problems with original Gleason (2005 & 2014 ISUP) Some patterns are extremely rare / not cancer Grade 1 likely adenosis Grade 2 Rare / Can t Dx on small needle Bx Some descriptions vague Cribriform 3 vs. Cribriform 4? Inter-observer variability; degraded prognostics Not all possible growth patterns represented Inter-observer variability; degraded prognostics!!! No rules for when more than two patterns Gleason Modifications: ISUP Scoring rules changed to better represent biology Bx, primary grade + worst = score, not secondary In Bx, if secondary lower grade and < 5%, ignore Prostatectomy, score discreet tumors of different grades separately. Recommend reporting percent > pattern 3. Modified Gleason -> Problems in Clinic: Grade Migration (perceived upgrading?) BEST score now 3+3 = 6 on scale 2-10. Confusing to patients Difficult to explain Patient anxiety precluding conservative management Patient and clinician frustration! 3+4=7 and 4+3=7 same score, but very different outcome!!! Grade Groups: Developed by Hopkins Group (J. Epstein) No formal name yet. Endorsed by WHO: WHO Grade Groups? Gleason Grade Groups (GGG). Based on using modified Gleason grades. ISUP 2005 and ISUP 2014 consensus conferences How does this system relate to Gleason grades and patient outcomes? How to apply this reporting system to practice? 19

Grade Groups (Epstein): Grade Group 1 = Gleason score < 7 Grade Group 2 = Gleason score 3+4 = 7 Grade Group 3 = Gleason score 4+3 = 7 Grade Group 4 = Gleason score 8 (4+4, 3+5, 5+3) Grade Group 5 = Gleason score > 8 (4+5, 5+4, 5+5) Validated in numerous f/u studies Endorsed by WHO and CAP Data: 4+3=7 and 4+4=8 same 4+5, 5+4 same, 5+5 worse (unpubl.) How to apply Grade Groups: ISUP modified Gleason Grades works best Developed using Biopsy with highest score Subsequent study showed that using overall Bx grade group or highest Bx grade group gave similar prognosis (Berney et al., Br J Cancer Apr 21, 2016 epub) Prostatectomy: If Grade 5 > 5%, then secondary Does not strictly follow ISUP! Probably works either way. Simple translation from Gleason score to GGG Clinicians can easily translate to grade groups Keeps report cleaner / less confusion PROSTATECTOMY Pierorazio, et al. Br J Urol Int 111: 753-60 (2013). Pierorazio, et al. Br J Urol Int 111: 753-60 (2013). 20

Grade Groups (Epstein): Grade Group 1 = Gleason score < 7 Grade Group 2 = Gleason score 3+4 = 7 Grade Group 3 = Gleason score 4+3 = 7 Grade Group 4 = Gleason score 8 (4+4, 3+5, 5+3) Grade Group 5 = Gleason score > 8 (4+5, 5+4, 5+5) Berney, et al. Br J Cancer (2016) Epub doi: 10.1038/bjc.2016.86 Simple translation from Gleason score to GGG Clinicians can easily translate to grade groups Keeps report cleaner / less confusion Improve communication with patients Will this replace Gleason? Continued Problems: Quantitative ( % of Gleason 4 and 5 ) Qualitative 3 vs. 4? (on a limited sample) Different outcomes for different types of 4? Discriminating some patterns of 4 from 5 difficult Stromal changes / cytology as a prognostic factors? 12, 000 pts. Sauter, et al., Eur Urol (Epub, 2017) 21

Qualitative: Expansile Cribriform Expansile Cribriform Prediction Based on Aggregate Data of Grade Group 2 Subanalyses McKenney (unpub. based on Kweldman et al., Eur J Cancer 66: 26 (2016)) Qualitative: Stromogenic Gleason 3B pattern? McKenney, et al., Am J Surg Pathol (2016) (accepted) McKenney, et al., Am J Surg Pathol 40: 1439 (2016) 22

McKenney, et al., Am J Surg Pathol 40: 1439 (2016) McKenney, et al., Am J Surg Pathol 40: 1439 (2016) 23

3 vs. 4? Decision can have major treatment implication. Active surveillance or not? Type of radiation? + / - anti-androgens. Problem areas: Tangential sectioning. Poorly formed glands. Potential aids: Level sections. Special stains: trichrome, Racemase (red chromogen). Future: 3D pathology? 24

3 vs. 4? Decision can have major treatment implication. Active surveillance or not? Type of radiation? + / - anti-androgens. Problem areas: Tangential sectioning. Poorly formed glands. Potential aids: Special stains: trichrome, Racemase (red chromogen). Level sections. Future: 3D pathology? 26

3D pathology: Light sheet microscopy (U. Washington). Summary: Improved power of Gleason Grading. Improved prognostics and consistency! Simple Grade Grouping system to improve communication with patients Areas for further improvement identified and under development. Quantifying the amount of tumor > pattern 3 (estab.) Subtyping pattern 4? Stromal characteristics and other histologic features? 3D pathology and other ancillary tools? Acknowledgements: Jesse McKenney: Cleveland Clinic Larry True: U. Washington Nick Reder: U. Washington Mike Bonham: Driver Inc. Sanjay Kakar: Brad Stohr: Karuna Garg: Nancy Greenland: 27

I m Hungry, let s eat Acknowledgements: Dr. Brad Stohr (MDPhD): Assistant Professor Dr. Nancy Greenland (MDPhD): Resident Physician (AP/CP) Dr. Jesse McKenney (MD): Cleveland Clinic 28

Epstein refs. Ductal: Tavora & Epstein, AJSP 32(7): 1060 (2008). Mucinous: Osunkoya, et al. AJSP 32(3): 468 (2008). Foamy: Nelson & Epstein, AJSP 20(4): 419 (1996). Pseudo: Humphrey, et al., AJSP 22(10): 1239 (1998). 29

McKenney, et al., Am J Surg Pathol 40: 1439 (2016) 30

DF Gleason, 1977 Gleason Modifications: ISUP Do not use Grades 1 or 2 (or use very sparingly) All carcinomas with cribriform growth = 4 Glomerulations = 4 but outcome data not in yet. Certain patterns (grades) better classified: Gleason growth pattern actually better than specific grades for some tumor morphologies. Tumor glands floating in mucin (mucinous carcinoma not all 4) Tumor with columnar cells (Ductal Ca) not always 4 Tumor cells with vacuoles seen in Gleason patterns 3, 4 or 5. Scoring rules changed to better represent biology In Bx, primary grade + worst = score, not secondary In Bx, if secondary lower grade and < 5%, ignore it. Prostatectomy, score discreet tumors of different grades separately. Recommend reporting percent tumor > pattern 3. Gleason Modifications: ISUP Do not use Grades 1 or 2 (or use very sparingly) All carcinomas with cribriform growth = 4 Glomerulations = 4 but outcome data not in yet. Certain patterns (grades) better classified: Gleason growth pattern actually better than specific grades for some tumor morphologies. Tumor glands floating in mucin (mucinous carcinoma not all 4) Tumor with columnar cells (Ductal Ca) not always 4 Tumor cells with vacuoles seen in Gleason patterns 3, 4 or 5. Scoring rules changed to better represent biology In Bx, primary grade + worst = score, not secondary In Bx, if secondary lower grade and < 5%, ignore it. Prostatectomy, score discreet tumors of different grades separately. Recommend reporting percent tumor > pattern 3. 31

Gleason Modifications: ISUP Do not use Grades 1 or 2 (or use very sparingly) All carcinomas with cribriform growth = 4 Glomerulations = 4 but outcome data not in yet. Certain patterns (grades) better classified: Gleason growth pattern actually better than specific grades for some tumor morphologies. Tumor glands floating in mucin (mucinous carcinoma not all 4) Tumor with columnar cells (Ductal Ca) not always 4 Tumor cells with vacuoles seen in Gleason patterns 3, 4 or 5. Scoring rules changed to better represent biology In Bx, primary grade + worst = score, not secondary In Bx, if secondary lower grade and < 5%, ignore it. Prostatectomy, score discreet tumors of different grades separately. Recommend reporting percent tumor > pattern 3. Images mucinous ductal 32