Consultant Histopathologist University Hospital of Wales · •esp. pattern 3 vs 4 ... Most common issue in Gleason grading Understanding rather than learning is the key! •Understand

Understanding

Gleason grading

Murali VarmaConsultant Histopathologist

University Hospital of Wales

Cardiff, UKECP2018

Gleason score

One of the most powerful prognostic parameters in prostate cancer

Why did we choose Gleason over other available grading systems?

1978 American Cancer SocietyProstate cancer grading workshops

Compared Gleason, Mostofi, Gaeta and Mayo systems



Recommended Gleason because it was “definable, simple, reproducible, and had compelling clinical relevance.”



Recommended Gleason because it was “definable, simple, reproducible, and had compelling clinical relevance.”

The solution

Understand what we are trying to achieve

• Not just learn the grading rules

Focus of lecture

The critical role of communication

• At least (more?) important than accurate grading

Pathologists and Surgeons

The communication gap

Surgeons view radiology

but not

pathology

Lecture outlineReporting issues

Borderline grades

• esp. pattern 3 vs 4


Borderline grades


Cores with different Gleason scores

• Global or worst?


Borderline grades



• Global or worst?

New grading system for prostate cancer


Borderline grades


New grading system for prostate cancer

Pattern 3 or 4?

Most common issue in Gleason grading

Gleason 6 or 7?

Most common issue in Gleason grading

Understanding rather than learning is the key!

• Understand what we are trying to achieve

• Rather than just learning how to grade

Gleason 6 or 7?

Gleason gradingA morphological continuum

Gleason 6 Gleason 7 Gleason 8

Gleason score 6 vs. 7

Morphological continuum

May have critical clinical consequences

• Radical therapy for Gleason 7?

Gleason 6 Gleason 7

Gleason scoreA biological continuum



Risk of EPE

1% 5% 10% 15% 20% 25% 30%



Risk of EPE

1% 5% 10% 15% 20% 25% 30%

At what risk of EPE should the cut offs be?



Risk of EPE

1% 5% 10% 15% 20% 25% 30%

At what risk of EPE should patient have radical therapy?

Borderline pattern 4

Good Gleason 7 behaves like bad Gleason 6

Gleason 6 Gleason 7

Good Gleason 7 behaves like bad Gleason 6

Borderline pattern 4

Gleason 6 Gleason 7

Reasonable to treat as either Gleason score 6 or 7

PSA

A clinical continuum with arbitrary cut-offs

PSA 10-20 intermediate risk; PSA >20 high-risk

Bone scan recommended if PSA >20

PSA




• PSA 20 not really different from PSA 21

PSA





• Reasonable to do bone scan if PSA 19

• Reasonable to omit bone scan if PSA 21

PSA





• Reasonable to do bone scan if PSA 19 (3 +4)

• Reasonable to omit bone scan if PSA 21 (3 + 3)

Borderline Gleason gradesDistinction

Biologically insignificant

Clinically significant

• Patient management based on Gleason score

How should we report borderline Gleason?

Reporting Gleason gradeWhy do we struggle?

Grade is a morphological and biological continuum

Continuous variable reported as a discrete variable

RCC StagingA biological continuum with arbitrary cut-offs

We report dimension in mm not just stage

pT2(>70mm)

pT1(up to 70mm)

We report dimension in mm not just stageBut grade reported as discrete variable

Gleason 6 Gleason 7

pT2(>70mm)

pT1(up to 70mm)

Gleason score 7

Not really different from Gleason 6

Very different from Gleason 6

Gleason 6 Gleason 7

Stratifying Gleason score 7

3+4 4+3

3+4 vs 4+3Not separate diseases

3+4 4+3

50% cut-off for 3+4 vs 4+3 based on convenience rather than data

3+4 vs 4+3Not separate diseases

3+4 4+3

Reasonable to treat as either 3+4 or 4+3

Path report does not permit distinctionGood or bad 3 + 4?

Stratifying Gleason score 7

Report percentage pattern 4

Gleason score 7Percentage pattern 4

0% <10% 40% 60% 90% >95%


Gleason score 3 + 4 = 7

Pattern 3 Pattern 4 Pattern 5

May be suitable for surveillance

Gleason score 3 + 4 = 7

Pattern 3 Pattern 4 Pattern 5

Not suitable for surveillance?

(50% pattern 4)


10% 50% 60% 90%

3+4 4+3

20% 30% 40% 80%70%

A biological continuum with arbitrary thresholdsPrecision not required

“In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups.”

Sauter, G et al. 2016;69:592-598.

Clinical Utility of Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens


Eyeball estimate

Nearest 10%

Important only near thresholds


<10%: not really different from bad 3+3

40%: not really different from good 4+3

60%: not really different from bad 3+4

90%: not really different from good 4+4

Gleason score 7Reporting percentage pattern 4

Reduces pathologist’s stress in borderline cases

Provides information to clinician

Shifts responsibility on to clinician

Gleason gradingA morphological and biological continuum

3+3 3+4 4+3 4+4 4+5 5+4 5+5

Gleason grading

Perfect precision not necessary or possible

3+3 3+4 4+3 4+4 4+5 5+4 5+5

Biopsy Gleason grading



Biopsy grade intrinsically inaccurate

• Sampling error

• Estimation of probability of true tumour grade in patient

Article first published online: 24 MAR 2016DOI: 10.1111/bju.13458 United States and Canadian Academy of Pathology annual

meeting 2015


meeting 2015

Bx: 4 + 4 = 8

Radical: ≈50% downgraded


meeting 2015

Bx: 4 + 4 = 8

Radical: ≈50% downgraded (20% primary pattern 3!)

Article first published online: 24 MAR 2016DOI: 10.1111/bju.13458 United States and Canadian Academy of Pathology

annual meeting 2015

Bx: 4 + 3 = 7Radical: ≈40% downgraded

Bx: 3 + 4 = 7Radical: ≈20% upgraded

3+3 3+4 4+3 4+4 4+5 5+4 5+5



Rough estimate of tumour Gleason score

How to report borderline grade

How to report borderline grade

Report lower grade

Really borderline 3+3 vs 3+4Report as 3+3: Rationale

Bx report: 3+4

• Patient definitely has pattern 4 in the prostate gland

Really borderline 3+3 vs 3+4Report as 3+3: Rationale

Bx report: 3+4

• Patient definitely has pattern 4 in the prostate gland

Bx report: 3+3

• Does not exclude pattern 4 in the patient

• May be pattern 4 in unsampled deeper level of core or elsewhere in the prostate gland

Really borderline 3+3 vs 3+4

Report as 3+3

• Consider adding comment: “foci bordering on pattern 4” in selected cases

Reviewing Gleason scoresMDT meetings etc

Try not to change borderline score



Consider whether reported score acceptable rather than how you would report it



Consider whether reported score acceptable rather than how you would report it

Reporting pathologist 3+3, my opinion: borderline 3+4

• I would report as 3+3 with foci bordering on pattern 4

•Biologically same as borderline 3+4

Gleason grading may become simpler

Cribriform pattern 4 more significant than fusion or poorly formed patterns of pattern 4

Modern Pathology 2016;29:630-636.

Modern Pathology 2017;30:1126-1132

Increased % pattern 4 is associated with cribriform growth pattern

Cribriform growth pattern is an independent parameter for biochemical recurrence (BCR) % pattern 4 did not independently predict BCR

Modern Pathology 2017;30:1126-1132

Increased % pattern 4 is associated with cribriform growth pattern

Cribriform growth pattern is an independent parameter for biochemical recurrence (BCR) % pattern 4 did not independently predict BCR

Gleason 7 grading may become simpler

Cribriform pattern 4 more significant than fusion or poorly formed pattern 4

Cribriform pattern 4 more predictive than % pattern 4

Cribriform pattern identification easier and more reproducible

Positive cores with different gradesWhich score to report?

Gleason pattern 3

Gleason pattern 4

3+4 3+4 3+4 3+3 4+4

Global: 3+4

Worst: 4+4


Uncommon scenario

• Global and Worst score same when:

• Only 1 core positive

• Global score 3+3



Uncommon scenario

• Global and Worst score same when:

• Only 1 core positive



Critical for some patients

• Global: 3+4; Worst: 4+4

Radical:2 tumours: 3 + 3 and 4 + 4(Worst score correct as prognosis will be of 4 + 4)

3+4 3+4 3+4 3+3 4+4

Gleason pattern 3

Gleason pattern 4

Gleason score:Global: 3 + 4Worst: 4 + 43+4 3+4 3+4 3+3 4+4

Gleason pattern 3

Gleason pattern 4

Another scenario

Radical:3 + 4 = 7(Worst will over-grade in this scenario)

3+4 3+4 3+4 3+3 4+4

Gleason pattern 3

Gleason pattern 4

Which Gleason scoreWorst or Global?

Several studies have concluded that the two are comparable

Which Gleason scoreWorst or Global?

Several studies have concluded that the two are comparable

However, Worst and Global different only in a minority of cases

• Hence any difference may be obscured

Concordance of “Case Level” Global, Highest, and Largest

Volume Cancer Grade Group on Needle Biopsy

Versus Grade Group on Radical Prostatectomy

Kiril Trpkov et al. Am J Surg Pathol (In Press)





2527 casesGlobal slightly better than Highest (60% vs 57%)






Global and Highest identical in 92%






Global and Highest different in 180 casesIn this subset, Global much better than Highest (62% vs 19%)

Global and Highest identical in 92%

How do clinicians use path data?

Journal of Clinical Pathology Published Online First: 02 May 2018. doi: 10.1136/jclinpath-2018-205093

Which Gleason score would you use?

A. Right apex: 3mm 10% GS 4 + 4 = 8

B. Right base: 6mm 80% GS 4 + 3 = 7

C. Left apex: 10mm 60% GS 3 + 3 = 6

D. Global GS 3 + 4 = 7

A. Worst score (least amount of tumour

B. Highest % (intermediate score)

C. Highest mm (lowest score)

D. Global Gleason score

Which Gleason score would you use?

A. Right apex: 3mm 10% GS 4 + 4 = 8

B. Right base: 6mm 80% GS 4 + 3 = 7

C. Left apex: 10mm 60% GS 3 + 3 = 6

D. Global GS 3 + 4 = 7

A. Worst score (least amount of tumour) 78%

B. Highest % (intermediate score) 12%

C. Highest mm (lowest score) 0%

D. Global Gleason score 10%

Surgeons view

radiology

but not pathology

Murali Varma, Dan Berney, Jon Oxley, Kiril Trpkov

Histopathology 2018;73:5-7.

Editorial: Gleason score assignment is the sole responsibility of the pathologist

Gleason Score assignment is the sole responsibility of the pathologist

Pathologist is in a better position than the clinician to decide which is the most appropriate score for an individual patient

Best score may be Global or Worst based on the pathologistsjudgment of the case

Gleason Score assignment is the sole responsibility of the pathologist

Morphology has also to be considered

Surgeons view

radiology

but not pathology

3+4 3+4 3+4 3+3 4+4

Gleason pattern 3

Poorly formed pattern 4

Cribriform pattern 4

3+4 3+4 3+4 3+3 4+4

Gleason pattern 3



Case level: Gleason 4 + 4 = 8

3+4 3+4 3+4 3+3 4+4

Gleason pattern 3


Case level: Gleason 3 + 4 = 7


Gleason score assignmentThere is no alternative to judgement

Pathologists already use their judgement to make critical decisions such as:

• Diagnosis of cancer

• Identification of Gleason pattern (3/4/5)

Gleason score assignmentThere is no alternative to judgement

Pathologists already use their judgement to make critical decisions such as:

• Diagnosis of cancer

• Identification of Gleason pattern (3/4/5)

Should be encouraged to use judgment to decide which Gleason score is best for an individual case

ISUP 2005/2014Recording Gleason score

Individual core/container GS mandatory

“Case-level” GS optional

Recording Gleason scoreAn alternative view

Case-level GS should be mandatory

Individual core/container GS optional

WHO 2016 grade groups1-5

1: Gleason score 2 - 6

2: Gleason score 3 + 4 = 7


4: Gleason score 8

5: Gleason score 9-10

“New” grading system

Not really a new grading system

•Different grouping of grades/scores

Gleason grade groupingsClinicians have always grouped scores

2-4, 5-7, 8-10

2-6, 7, 8-10

2-6, 3+4, 4+3, 8-10

2-6, 3+4, 4+3, 8, 9-10 (WHO 2016)


Can be derived from reported Gleason score

• Little additional work for pathologist

• No additional information for urologist


Can be derived from reported Gleason score

• Little additional work for pathologist

• No additional information for urologist

• Clinically very useful

Patients read path reports

Gleason grading issue

Gleason scores range from 2-10

Gleason score 6 misinterpreted by patients as intermediate grade

Minimum Gleason score in bx is 6





4: Gleason score 8






4: Gleason score 8


Novel feature first proposed by Jonathan Epstein

Patients read path reports

Gleason gradingA paradigm shift

Pathology reporting practice changed to directly address change in patient practice

Gleason gradingA paradigm shift

Pathology reporting practice changed to directly address change in patient practice

• Uropathologists putting patients before science!

Take Home Messages

Grade is a morphological and clinical continuum

Either treatment option reasonable for borderline grades

Critical to communicate that a patient’s grade is borderline so that he can make an informed decision

Take Home Messages

Major changes in prostate cancer grading were in 2005

Grade groups have limited impact on pathology/clinical practice

Inclusion of Grade Groups in pathology reports very valuable for patients

Thank You

for not yawning

Thank You for your attention

Documents

Consultant Histopathologist University Hospital of Wales · •esp. pattern 3 vs 4 ... Most common issue in Gleason grading Understanding rather than learning is the key! •Understand