(Endometrial Intraepithelial Neoplasia): Improved Criteria ... · PDF file Endometrial...
date post
16-Oct-2020Category
Documents
view
2download
0
Embed Size (px)
Transcript of (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · PDF file Endometrial...
EIN (Endometrial Intraepithelial Neoplasia):
Improved Criteria for diagnosing endometrial precancer
EIN (Endometrial Intraepithelial Neoplasia):
Improved Criteria for diagnosing endometrial precancer
Stanley J. Robboy, MD, FCAP, FFPath FRCPI (Hon), FRCPath (UK, Hon)
Professor of Pathology, Duke University Past-President, College American Pathologists
Feature Endometrioid Non-Endometrioid
Histotype Endometrioid,
Secretory, Squamous
Serous, Clear cell,
Carcinosarcoma Behavior Indolent Aggressive
Risk factors Hormonal None Precursor “Hyperplasia” Serous EIC
Types: Endometrial Cancers
Retrospective Studies (Hertig, 1949)
Retrospective Studies (Hertig, 1949)
Time from old biopsies to CA Interval Finding >15 yr Normal
> 6 yr Cystic hyperplasia < 5 yr Adenomatous/Atyp hyperplasia CIS
Endometrial Hyperplasia Common terms
Endometrial Hyperplasia Common terms
• Simple v. Complex v. Atypia • Cystic atrophy v. Hyperplasia • Disordered prolif v Simple hyperplasia • Mild, Mod, Marked (3Ms)
–with/without Atypia • Adenomatous, Anaplasia & CIS
WHO94 Endometrial Hyperplasia System WHO94 Endometrial Hyperplasia System
Criteria Glandular complexity
Nuclear atypicality
WHO94 Endometrial Hyperplasia System WHO94 Endometrial Hyperplasia System
Simple →
Complex →
A R C H I T E C T U R E
No atypia With atypia
No atypia With atypia
WHO94 Endometrial Hyperplasia System WHO94 Endometrial Hyperplasia System
No atypia→
Atypia →
C Y T O L O G Y
Simple Complex
Simple Complex
Progression to cancer Nested case control (2008)
Progression to cancer Nested case control (2008)
Hyperplasia Relative Risk
Simple 2.0
Complex 2.8
Atypical 14.0
Lacey 2008
Problems in diagnosis: GOG experience
Problems in diagnosis: GOG experience
Community cases
submitted as atypical
hyperplasia
40% Benign/Hyper 30% Atyp Hyper 30% Cancer
Trimble, Gyn Onc 2004
Problems in diagnosis: GOG experience
Problems in diagnosis: GOG experience
Expert gynecologic pathologists
disagree among
themselves
60% disagreement
Zaino, USCAP 2004
EIN: Endometrial Intraepithelial Neoplasia
EIN: Endometrial Intraepithelial Neoplasia
Conceptual shift in thinking
EIN – Conceptual ImportEIN – Conceptual Import
• Genetic changes key, not estrogen • Computer measurable (Reproducible) • Weeds out cases that otherwise might
likely be treated • May identify latent cases
Monoclonal OriginMonoclonal Origin • Point origin and expansile growth
Select relevant fields Size changes over time
• Lesion contrasts with normal Compare internally
• Ratio glands to stroma – Volume % glands
• Length of basement membrane – ‘Outer surface density’ of glands
• Nuclear pleomorphism – Std deviation of shortest nuclear diameter
EINEIN • Excessive glands (glands > stroma) • Abnormal architecture
– Excessive branching, out- or inward Complexity & papillary snouts
• Cytologic atypia – Nuclei pleomorphic, dyspolarized,
Irregularly stratified – Nucleoli uniformly prominent – Cytoplasm eosinophilic
+ 0.0439 x (Volume % Stroma) – 0.1592 x (Outer Surface Density glands) – 3.9934 x Ln (Std Dev Shortest Nuclear Axis) + 0.6229
0 +1 -4 +5
Progression risk: 40-60% 25-30% ~ 0%
Frequency: 15-25% 5% 65%
Baak 1988
Contribution to D-ScoreContribution to D-Score ß Volume % Glands 65% ß Perimeter Basement Membr 25% ß Standard Deviation
Shortest Nuclear Axis 10%
ARCHITECTURAL FEATURES MORE IMPORTANT
THAN CYTONUCLEAR FEATURES
Volume Percentage Stroma
Normal GlandEIN Gland Hyperplasia
OUTER SURFACE DENSITY GLANDS
Basal Membrane = Outer Surface Density Increases from Normal ‡ Hyperplasia ‡ EIN
AH (18/59)
0
20
40
60
80
100
Fo llo
w up
, M on
th s
CH (2/22)
SH (3/95)
Outcome Cancer No Cancer
Clinical Outcome of 176 WHO “Hyperplasias”
Mutter, 2002
20
40
60
80
100
Fo llo
w up
, M on
th s
EIN (22/65)
No EIN (1/111)
Outcome Cancer No Cancer
Clinical Outcome of 176 “Hyperplasias” Rediagnosed by EIN Criteria
Mutter 2002
Timing - a critical flawTiming - a critical flaw Concurrent
Appears in 1st year
Progression Appears in 2nd or later years
Concept of ProgressionConcept of Progression • Concurrent:
Tumor appears in 1st year, i.e., < 1 yr follow-up 197 women
• Progression: Appears > 1 year
477 women (median 48 mo, max 22 yrs)
Progression – WHO 94Progression – WHO 94 1 yr %
0.7 9 7
20
Progression – EIN D-scoreProgression – EIN D-score 1 0 1 yr %
0.6 29
Pr ob
ab ili
ty o
f R em
ai ni
ng
W ith
ou t P
ro gr
es si
on 1.0
.8
.6
.4
.2
.0 0 18012060
HR D-Score >1 vs. 0-1= 28 HR D-Score >1 vs 1
D-Score 0-1
D-Score 12 mo) From Baak, Mutter, Robboy et al, Cancer June 2005
EIN
Proliferative
31%
Complex Atypical
Simple Non-Atypical
Complex Non-Atypical
Endometrial Intraepithelial Neoplasia
52% 43%
20%
Baak et al 2005
Simple Atypical
36%
N=56 N=67 N=65 N=188
25%
25% 19%
EIN No EIN
2 of every 3 “hyperplasia” cases are benign
EIN: ICD-9EIN: ICD-9 As of January 1, 2010
621.34 Benign endometrial hyperplasia
621.35 Endometrial intraepithelial neoplasia [EIN]
EIN Reproducibility
Usubutum A et al
Modern Pathol 25: 877-884, 2012
Questionaire, 20 reviewers
Terminology preferred WHO 80% Read Robboy’s PFRT Yes 90% Visit EM.org Website Yes 90% EIN system easy to learn Yes 85% Easy to apply Yes 70%
Pathologist Style Group
C as
e
20 28 36 29 40 37 64 18 27 30 09 21 04 31 60 48 63 17 08 16 32 38 19 14 15 26 11 39 54 62 03 23 61 44 25 06 51 45 07 22 46 42 24 58 56 52 49 43 33 12 05 01 10 13 41 47 50 53 57 59 55 35
T S R N H J D K B I C G O P Q M E FAL GREEN YELLOW RED
Expert Concensus
Benign, non-EIN EIN Cancer
Diagnosis
No Data
Usubutun et al, 2012
Community: "Expert" EIN Diagnostic Reproducibility
Expert Consensus kappa=0.74 Community-Expert: 20 pathologists 79% agree w expert. Community to expert kappas= 0.72 (.45-.84)
Discordant Cases Defines Pathologist Style
Ref Dx Red Green Explanation OverDx UnderDx
EIN EIN B9 Small focus, EIN in anov Polyp; Loose, Subtle
B9 EIN B9 Fragment, Shattered, Thick
PTEN & mutationsPTEN & mutations
PAX2 (10q24)PAX2 (10q24) • Transcription factor • Embryonic expression required for:
Kidney Mesonephric structures Paramesonephric ducts
• 5-fold reduced in endometrial Ca
PAX2 knockout leads to Mullerian and renal atresia
Dressler, 1995
08-111EIN: H&EEIN: PTENEIN: PAX2
H&E PTEN PAX2
EIN
normal background
*
+
*
+
*
+
*
+
* *
+
+
08-111
Coinactivated PAX2 & PTEN in EIN
Mutter, 2010
PAX2 & PTEN null rates by dx
Mutter, 2010
PE (normal)
EIN Cancer
PAX2 null 36% 71% 77% PTEN null 49% 44% 68% Both express 36% 15% 10%
Atypical Hyperplasia kappa=0.34-0.47
= EIN kappa=0.54-0.62
True Precancer
Target Interobserver Reproducibility Improved
WHO-2014 (New) Endometrial Hyperplasia
System
WHO-2014 (New) Endometrial Hyperplasia
System Benign
Hyperplasia without atypica Precancer
Atypical hyperplasia / Endometrioid Intraepithelial Hyperplasia
AcknowledgementsAcknowledgements • Jan Baak, MD, Professor of Pathology
Stavanger University Hospital, Norway University of Munich, Germany
• George Mutter, MD, Professor of Pathology Brigham & Womens’ Hospital Harvard University Medical School Also see www.endometrium.org
http://www.endometrium.org
