Understanding Gleason grading Murali Varma Consultant Histopathologist University Hospital of Wales Cardiff, UK ECP2018
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
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.”
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.”
Focus of lecture
The critical role of communication
• At least (more?) important than accurate grading
Lecture outlineReporting issues
Borderline grades
• esp. pattern 3 vs 4
Cores with different Gleason scores
• Global or worst?
Lecture outlineReporting issues
Borderline grades
• esp. pattern 3 vs 4
Cores with different Gleason scores
• Global or worst?
New grading system for prostate cancer
Lecture outlineReporting issues
Borderline grades
Cores with different Gleason scores
New grading system for prostate cancer
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 score 6 vs. 7
Morphological continuum
May have critical clinical consequences
• Radical therapy for Gleason 7?
Gleason 6 Gleason 7
Gleason 6 Gleason 7 Gleason 8
Gleason scoreA biological continuum
Risk of EPE
1% 5% 10% 15% 20% 25% 30%
Gleason 6 Gleason 7 Gleason 8
Gleason scoreA biological continuum
Risk of EPE
1% 5% 10% 15% 20% 25% 30%
At what risk of EPE should the cut offs be?
Gleason 6 Gleason 7 Gleason 8
Gleason scoreA biological continuum
Risk of EPE
1% 5% 10% 15% 20% 25% 30%
At what risk of EPE should patient have radical therapy?
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
A clinical continuum with arbitrary cut-offs
PSA 10-20 intermediate risk; PSA >20 high-risk
Bone scan recommended if PSA >20
• PSA 20 not really different from PSA 21
PSA
A clinical continuum with arbitrary cut-offs
PSA 10-20 intermediate risk; PSA >20 high-risk
Bone scan recommended if PSA >20
• PSA 20 not really different from PSA 21
• Reasonable to do bone scan if PSA 19
• Reasonable to omit bone scan if PSA 21
PSA
A clinical continuum with arbitrary cut-offs
PSA 10-20 intermediate risk; PSA >20 high-risk
Bone scan recommended if PSA >20
• PSA 20 not really different from PSA 21
• 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
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
Gleason score 3 + 4 = 7
Pattern 3 Pattern 4 Pattern 5
Not suitable for surveillance?
(50% pattern 4)
Gleason score 7Percentage 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
Gleason score 7Percentage pattern 4
<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
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
Article first published online: 24 MAR 2016DOI: 10.1111/bju.13458 United States and Canadian Academy of Pathology annual
meeting 2015
Bx: 4 + 4 = 8
Radical: ≈50% downgraded
Article first published online: 24 MAR 2016DOI: 10.1111/bju.13458 United States and Canadian Academy of Pathology annual
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
Biopsy Gleason grading
Perfect precision not necessary or possible
Rough estimate of tumour Gleason score
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
Reviewing Gleason scoresMDT meetings etc
Try not to change borderline score
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
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
Positive cores with different gradesWhich score to report?
Uncommon scenario
• Global and Worst score same when:
• Only 1 core positive
• Global score 3+3
• Global score 3+4
Positive cores with different gradesWhich score to report?
Uncommon scenario
• Global and Worst score same when:
• Only 1 core positive
• Global score 3+3
• Global score 3+4
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
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)
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%)
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%
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 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%
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
Case level: Gleason 4 + 4 = 8
3+4 3+4 3+4 3+3 4+4
Gleason pattern 3
Poorly formed pattern 4
Case level: Gleason 3 + 4 = 7
Cribriform pattern 4
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
3: Gleason score 4 + 3 = 7
4: Gleason score 8
5: Gleason score 9-10
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)
“New” grading system
Can be derived from reported Gleason score
• Little additional work for pathologist
• No additional information for urologist
“New” grading system
Can be derived from reported Gleason score
• Little additional work for pathologist
• No additional information for urologist
• Clinically very useful
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
WHO 2016 grade groups1-5
1: Gleason score 2 - 6
2: Gleason score 3 + 4 = 7
3: Gleason score 4 + 3 = 7
4: Gleason score 8
5: Gleason score 9-10
WHO 2016 grade groups1-5
1: Gleason score 2 - 6
2: Gleason score 3 + 4 = 7
3: Gleason score 4 + 3 = 7
4: Gleason score 8
5: Gleason score 9-10
Novel feature first proposed by Jonathan Epstein
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