10/21/2014
The 2005 International Society of
Update on Grading Prostate Cancer
Jonathan I. Epstein, MD
Department of Pathology
The Johns Hopkins Hospital
WHY THE NEED FOR A CONSENSUS ON
GLEASON GRADING?
Urological Pathology (ISUP) Consensus
Conference on Gleason Grading of
Prostatic Carcinoma
The American Journal of Surgical Pathology: Volume 29.
September 2005 pp 1228-1242
Epstein, Jonathan I ; Allsbrook, William C Jr; Amin,
Mahul B; Egevad, Lars L and the ISUP Grading
Committee
Gleason’s Era
• More advanced clinical disease
• Fewer RPs which were not processed in entirety
– Grading of multiple nodules
– Tertiary patterns
• Needle biopsy only a few thick cores
– Grading thin needle cores
– Grading multiple cores from different sites
• Lesions diagnosed differently with more modern tests
• New entities
Reporting Grade
• “Gleason grade 4” - ? Gleason pattern 4 (ie 4+4=8) or
2+2=4
• “Gleason grade 3/5” - ? Gleason pattern 3 out of 5
patterns (ie. 3+3=6) or 3+5=8
• Gleason score 3+4=7 (preferred method even if
limited cancer)
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Gleason Score 2+2=4

Gleason Score 3+3=6

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Gleason Score 3+4=7/4+3=7

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Gleason Score 4+4=8

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Gleason Score 9-10

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Grading Variants of Prostate

Adenocarcinoma
Same rule as grading usual prostate adenocarcinoma
based on underlying grade pattern, except small cell
carcinoma.

• Individual well-formed glands – pattern 3

• Cribriform – pattern 4
• Individual cells or necrosis – pattern 5

Small Cell Carcinoma

Small cell carcinoma of the prostate has unique

histological, immunohistochemical, and clinical
features, which differ from those associated with
Gleason pattern 5 prostatic acinar carcinoma, such
that small cell carcinoma should not be assigned a
Gleason grade.

Foamy Gland Cancer

• Most will be Gleason score 3+3=6

• Occasionally high grade foamy cancer

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Foamy Gland: Pattern 3 Foamy Gland: Pattern 4

Foamy Gland: Pattern 5

Ductal Adenocarcinoma

• Cribriform/papillary ductal adenocarcinomas should be

graded as Gleason score 4+4=8, while retaining the
diagnostic term of ductal adenocarcinoma to denote their
unique clinical and pathological findings.

• This can be achieved by diagnosing such a tumor as

“prostatic ductal adenocarcinoma (Gleason score 4+4=8).”

• PIN-Like ductal adenocarcinoma graded 3+3=6.

• Duct adenocarcinoma with necrosis grades as Gleason

pattern 5.

Ductal Adenocarcinoma: Gleason Pattern 4 Ductal Adenocarcinoma: Gleason Pattern 4

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Gleason Pattern 3

Vacuoles

• Mostly Gleason patterns 4 & 5

• Occasionally Gleason pattern 3

Vacuoles: Pattern 3 Vacuoles: Pattern 4

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Vacuoles: Pattern 5

Colloid (Mucinous) Carcinoma

Most Gleason pattern 4

Some Gleason pattern 3

Mucinous Cancer: Pattern 4 Mucinous Cancer: Pattern 3

Mucinous Cancer: Gleason Score 3+4=7

Pseudohyperplastic Adenocarcinoma

All graded as 3+3=6

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Pseudohyperplastic: Pattern 3

Mucinous Fibroplasia
(Collagenous Micronodules)

One should try to subtract away the mucinous

fibroplasia and grade the tumor based on the underlying
glandular architecture. The majority of these cases would
accordingly be graded as Gleason score 3+3=6.

Mucinous Fibroplasia: Pattern 3 Mucinous Fibroplasia: Pattern 3

Mucinous Fibroplasia: Pattern 4

Glomeruloid Structures

• Both large and small glomeruloid structures are

variations of cribriform glands where the cribriform
structure does not extend fully across the glandular
lumen.

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Glomeruloid Glands: Pattern 4 Glomeruloid Glands: Pattern 4

Reporting Rules for Gleason Grading

REPORTING SECONDARY PATTERNS OF

LOWER GRADE WHEN PRESENT TO A
LIMITED EXTENT
<5%

4 3
In the setting of high grade cancer one should ignore
lower grade patterns if they occupy less than 5% of
the area of the tumor. Standard:
3 4+3=7 4

Consensus: 4 + 4 = 8

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REPORTING SECONDARY PATTERNS OF

HIGHER GRADE WHEN PRESENT TO A
LIMITED EXTENT (NEEDLE)
<5%

High grade tumor of any quantity on needle biopsy, 3 4

as long as it was identified at low to medium

magnification should be included within the Gleason
score. 3 4

Consensus: 3 + 4 = 7

TERTIARY GLEASON PATTERNS (N)

Patterns 3, 4, and 5 in various proportions, classify as high 4

grade (Gleason score 8-10) given the presence of high grade 60% 30% 10%
tumor (patterns 4 and 5). 3 4 5

Both the primary pattern and the highest grade should be

recorded. Standard: 3 + 4 = 7
Consensus: 3 + 5 = 8
Gleason score 3+4 and a tertiary pattern 5 = Gleason score
3+5=8.

NEEDLE BIOPSIES WITH DIFFERENT CORES DIFFERENT GRADES NEEDLE BIOPSY WITH DIFFERENT CORES
Greatest importance when >1 cores pure high grade cancer (i.e. Gleason SHOWING DIFFERENT GRADES
score 4+4=8) and other cores pattern 3 (3+3=6, 3+4=7, 4+3=7) cancer.

Highest or Average Gleason Score
• Gleason score 4+4=8 on >1 cores with pattern 3 in other cores more
likely higher stage and higher grade at RP, comparable to pure 4+4=8.
• Several studies show that the highest Gleason score correlates better
with RP grade and stage as opposed to the most common (global)
Gleason score.
One should assign individual Gleason scores to separate cores
as long as the cores were submitted in separate containers or
the cores were in the same container yet specified by the
urologist as to their location (ie. by different color inks).
Assigning a global (composite) score is optional.

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Gleason Score 2-4 on Needle

Low Grade Prostate Cancer Does Exist
• Diagnosis of Gleason 2-4 should not be made on needle.
• Transition zone
• 1) Poor reproducibility among experts for lower grade
tumors.
• Small foci

• 2) Correlation with the prostatectomy score for Gleason 2-

4 tumors is poor and up to 50% of the corresponding
prostatectomies may have extraprostatic extension.
• 3) Gleason 2-4 may misguide clinicians and patients into
believing that there is an indolent tumor.
• Seen on TURP – often indicates “insignificant” cancer
• Rarely sampled on needle biopsy – not indicate
“indolent” tumor

Reporting of Gleason Grade in RPs

REPORTING MINOR HIGHER GRADE
• Each dominant tumor focus should be graded PATTERNS IN A RP
separately. For example: 2 tumor nodules – One PZ
4+4=8 with separate TZ 2+2=4. Give two scores and
not call 4+2=6. Tumor nodule having >95% Gleason pattern 3 and <5%
pattern 4, we report as Gleason score 3+3=6 with a
minor component of Gleason pattern 4.
• Typically only the largest tumor foci are graded. Not
necessary to report small multifocal lower grade
cancer. Better prognosis of <5% vs. 5%-50% pattern 4.

• Exception when there is a smaller tumor focus of

higher grade, report this Gleason score.

MINOR (TERTIARY) GLEASON

Tertiary Gleason Patterns
PATTERNS IN A RP
• 3+3=6 with Tertiary prognosis between 3+3=6 & 3+4=7.

For a radical prostatectomy specimen one assigns the • 3+4=7 with Tertiary prognosis between 3+4=7 & 4+3=7.
Gleason score based on the primary and secondary patterns
with a comment as to the minor (tertiary) pattern
• 4+3=7 with Tertiary prognosis between 4+3=7 & 4+4=8

• 4+4=8 with Tertiary prognosis similar to Gleason score 9-10

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Prognosis on Needle Biopsy

& Impact on Therapy

Correlation Needle & RP Grade

Risk of Upgrading
Needle RP
6 3+4 (22%) • Increased clinical stage
3+4=7 16% (3+3); 16% (4+3) • Increased PSA
4+3=7 39% (3+4); 40% (4+3) • Increased cancer on biopsy
8 26% (4+3); 30% (8); 25% (9-10)
• Decreased biopsy sampling

• Decrease prostate volume

Biopsy Gleason Score <6 vs. >7 Biopsy Gleason Score 3+4 vs. 4+3

• Active surveillance vs. definitive treatment Radiation therapy

vs.
• Brachytherapy vs. XRT + brachytherapy Hormones + radiation therapy

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Prognosis at Radical Prostatectomy:

Biopsy Gleason Score 8 vs. 9-10
Proposal for a New Grading System
Surgery vs. Radiation

b. Gleason cribriform grade 3 prostatic adenocarcinoma.

Changes to the Gleason Grading System

1. Poorly formed glands now Gleason pattern 4

2. All cribriform patterns now called pattern 4

Only 10 of 270 (3.7%) cases of Gleason had a primary

grade pattern 4, and 4 was a secondary grade pattern
in only 20 of 270 (7.4%) cases – currently pattern 4
much more prevalent.

McNeal J, Yemoto C. Am J Surg Pathol 1996; 20:802-14

Changes to the Gleason Grading System

3. Primary pattern + worst (not secondary) pattern on needle
biopsy
4. Ignore very small amounts of lower grade cancer on
biopsy in the setting of extensive high grade cancer
5. Codified that Gleason patterns 1 and 2 not made on biopsy
Updates to the Gleason System
• Grading of existing variants of prostate cancer –
small cell; mucinous; ductal; signet ring cell-like;
Grading newly described variants – foamy;
pseudohyperplastic; cancers with treatment affect
• Grading tertiary patterns on RP
• Grading multiple cores from different sites

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Problems with Gleason Grading

Updates to the Gleason System
System Scale
• Provided guidelines how to grade different nodules of • 6 is the lowest grade reported although the scale goes
different grades in radical prostatectomies from 2-10

• Gleason 7 is not homogeneous: 4+3=7 has a much

worse prognosis than 3+4=7

• Gleason 8-10 is often considered as one group - high

grade disease

Prognostic Grade Grouping

RP Data From 5 Institutions

• Gleason score 2-6, Prognostic Grade Group I/V • Since 2005 – Modified Gleason grades

• Gleason score 3+4=7, Prognostic Grade Group II/V
• Gleason score 4+3=7, Prognostic Grade Group III/V
• Gleason score 8, Prognostic Grade Group IV/V
• Gleason score 9-10, Prognostic Grade Group V/V
• University of Pittsburgh – Joel Nelson, Anil Parwani
• MSKCC – Victor Reuter, Samson Fine, Andrew Vickers,
James Eastham
• CCF – Christina Magi-Galluzzi, Eric Klein
• Karolinska – Lars Egevad, Peter Wiklund
• Johns Hopkins – Jonathan Epstein, Misop Han

Meta-Analysis Follow-up

Hosp | Freq. Percent Cum.

• Mean follow-up to progression 2.0 years with median
------------+-----------------------------------
1.1 years.
Pittsburgh | 2,088 10.96 10.96
Karolinska | 3,763 19.75 30.71
Hopkins | 5,483 28.77 59.48 • Mean follow-up without progression 3.8 years with
Memorial | 5,535 29.05 88.53 median 3.1 years.
CCF | 2,186 11.47 100.00
------------+-----------------------------------
Total | 19,055 100.00 •

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5 Year Biochemical Risk Free Survival

Group Gleason BRFS 95% Confidence
Intervals

1 3+3=6 97.5% 97.0%-98.0%

2 3+4=7 93.1% 92.4%-93.8%
3 4+3=7 78.1% 76.0%-80.1%
4 4+4=8 63.6% 59.1%-67.7%
5 9-10 48.9% 44.1%-53.5%

Hazard Ratios Relative to Group 1 Conclusions

1. Based on over 19,000 RP cases from Karolinska,
Group 1 1.0 MSKCC, JHH, U. Pitt., and CCF a new grading
Group 2 2.6 system composed of 5 grades accurately stratifies
prognosis.
Group 3 8.5
Group 4 16.8
2. New grading system has as its foundation the
Group 5 29.3
Gleason system but based on extensive subsequent
research incorporates significant changes in its
definition and application.

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