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Grading Prostate Cancer: Recommendation rating of D Recent Changes - - PowerPoint PPT Presentation

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UCSF UCSF USPSTF: 2012 Report on serum PSA Screening Grading Prostate Cancer: Recommendation rating of D Recent Changes and Reduced screening, Reduced biopsies, reduced incidence Refinements Refinements currently occurring in

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UCSF

USPSTF: 2012 Report on serum PSA Screening Recommendation rating of “D”

  • Reduced screening, Reduced biopsies, reduced incidence
  • Refinements currently occurring in 2017. WHY?

Eapen, et al., Curr. Op. Urol. 27(3): 205-9 ( May 2017) UCSF

Grading Prostate Cancer: Recent Changes and Refinements

UCSF Current Issues in Pathology May 25, 2017 Jeffry P. Simko, PhD, MD

Professor of Clinical Pathology UCSF Departments of Urology, Radiation Oncology and Anatomic Pathology

UCSF

Disclosures:

  • GenomeDx: Consultant
  • 3D Biopsy: Advisory Board, Consultant
  • 3 Scan: Advisory Board, Consultant

UCSF

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
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Grading Cancers of the Prostate:

  • Prostatic adenocarcinoma (> 99%)

– Acinar type

  • atrophic, foamy, pseudohyperplastic, others

– Ductal type – Mucinous type – Vacuolated type (signet ring cell-like)

  • 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 UCSF

Grading Systems (more than 40):

Architecture vs. Cytology vs. Combinations

Urol Surg Pathol 1st Ed. (Elsevier, Bostwick & Eble: 1996)

UCSF

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!

  • Profound effects on Management

– Active surveillance ( No pattern 4 ? ) – Type of radiation?

  • + / - Anti-androgens

– Adjuvant therapy post prostatectomy ?

UCSF

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
  • 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. )

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DF Gleason, 1966

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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

UCSF

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)

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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UCSF UCSF UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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Gleason pattern 3:

  • Individual glands infiltrating benign
  • Irregular distribution (not uniform)
  • Regular distribution OK if B9 incorporated

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF UCSF

DF Gleason, 1977

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF UCSF

Gleason Pattern 4:

  • Gland fusion

– Cribriform (glomerulations) – Sinuating small glands in chains or cords – Poorly formed glands ?

  • High grade tumor

(changes Rx options)

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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UCSF UCSF UCSF Jesses comments. UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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Gleason Pattern 5:

  • Single cells, solid sheets or necrosis in 4
  • Vacuoles are not pattern 4!

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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

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UCSF UCSF UCSF UCSF

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

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Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF

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).

UCSF

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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.

UCSF UCSF

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UCSF UCSF UCSF treated issues. UCSF

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

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UCSF Subtypes foamy, muycinous, pseudohyperplastic, atrophic. UCSF

Gleason Modifications: ISUP

  • International Society of Urologic Pathologists

Consensus Meetings: 2005, 2014

– 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 )

UCSF

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

UCSF

RARE

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UCSF

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 growth patterns represented (glomerulations)

– Inter-observer variability; degraded prognostics

  • No rules for when more than two patterns

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF Jesses comments. UCSF

RARE

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UCSF

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

UCSF

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.

UCSF

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!!!

UCSF

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?
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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
  • UCSF Data:

– 4+3=7 and 4+4=8 same – 4+5, 5+4 same, 5+5 worse (unpubl.) UCSF

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 UCSF Pierorazio, et al. Br J Urol Int 111: 753-60 (2013).

PROSTATECTOMY

UCSF Pierorazio, et al. Br J Urol Int 111: 753-60 (2013).

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Berney, et al. Br J Cancer (2016) Epub doi: 10.1038/bjc.2016.86

UCSF

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)
  • 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? UCSF

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?

UCSF 12, 000 pts. Sauter, et al., Eur Urol (Epub, 2017)

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Qualitative: Expansile Cribriform

  • Expansile Cribriform

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McKenney (unpub. based on Kweldman et al., Eur J Cancer 66: 26 (2016))

Prediction Based on Aggregate Data

  • f Grade Group 2 Subanalyses

UCSF

McKenney, et al., Am J Surg Pathol (2016) (accepted)

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Qualitative: “Stromogenic”

  • Gleason 3B pattern?

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

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

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

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002) Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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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? UCSF UCSF UCSF

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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? UCSF UCSF UCSF

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3D pathology:

  • Light sheet microscopy (U. Washington).

UCSF

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? UCSF

Acknowledgements:

  • Jesse McKenney: Cleveland Clinic
  • Larry True: U. Washington
  • Nick Reder: U. Washington
  • Mike Bonham: Driver Inc.
  • Sanjay Kakar: UCSF
  • Brad Stohr: UCSF
  • Karuna Garg: UCSF
  • Nancy Greenland: UCSF
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UCSF UCSF

I’m Hungry, let’s eat

UCSF UCSF

Acknowledgements:

  • Dr. Brad Stohr (MDPhD): UCSF Assistant Professor
  • Dr. Nancy Greenland (MDPhD): UCSF Resident Physician (AP/CP)
  • Dr. Jesse McKenney (MD): Cleveland Clinic
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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).

UCSF

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UCSF UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

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

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UCSF UCSF

DF Gleason, 1977

UCSF

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.

UCSF

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.
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UCSF

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.

UCSF Images mucinous ductal

Prostate Bx. Int. 3rd ed. (Epstein & Yang, 2002)

UCSF UCSF

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UCSF