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
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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 UniversityPast-President, College American Pathologists
Feature Endometrioid Non-Endometrioid
HistotypeEndometrioid,
Secretory, Squamous
Serous, Clear cell,
CarcinosarcomaBehavior Indolent Aggressive
Risk factors Hormonal NonePrecursor “Hyperplasia” Serous EIC
Types: Endometrial Cancers
Retrospective Studies(Hertig, 1949)
Retrospective Studies(Hertig, 1949)
Time from old biopsies to CAInterval Finding>15 yr Normal
> 6 yr Cystic hyperplasia< 5 yr Adenomatous/Atyp hyperplasia CIS
Endometrial HyperplasiaCommon terms
Endometrial HyperplasiaCommon 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 SystemWHO94 Endometrial Hyperplasia System
CriteriaGlandular complexity
Nuclear atypicality
WHO94 Endometrial Hyperplasia SystemWHO94 Endometrial Hyperplasia System
Simple →
Complex →
ARCHITECTURE
No atypiaWith atypia
No atypiaWith atypia
WHO94 Endometrial Hyperplasia SystemWHO94 Endometrial Hyperplasia System
No atypia→
Atypia →
CYTOLOGY
SimpleComplex
SimpleComplex
Progression to cancerNested case control (2008)
Progression to cancerNested 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 shiftin 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 fieldsSize changes over time
• Lesion contrasts with normalCompare 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§ Volume % Glands 65%
§ Perimeter Basement Membr 25%
§ 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 à Hyperplasia à EIN
AH(18/59)
0
20
40
60
80
100
Follo
wup
, Mon
ths
CH(2/22)
SH(3/95)
OutcomeCancerNo Cancer
Clinical Outcome of 176 WHO “Hyperplasias”
Mutter, 2002
20
40
60
80
100
Follo
wup
, Mon
ths
EIN(22/65)
No EIN(1/111)
OutcomeCancerNo Cancer
Clinical Outcome of 176 “Hyperplasias” Rediagnosed by EIN Criteria
Mutter 2002
Timing - a critical flawTiming - a critical flawConcurrent
Appears in 1st year
ProgressionAppears in 2nd or later years
Concept of ProgressionConcept of Progression• Concurrent:
Tumor appears in 1st year, i.e., < 1 yr follow-up197 women
• Progression:Appears > 1 year
477 women (median 48 mo, max 22 yrs)
Progression – WHO 94Progression – WHO 94<1 yr
%SH 4CH 9SAH 20CAH 53
>1 yr%
0.797
20
Progression – EIN D-scoreProgression – EIN D-score<1 yr
Score %>1 0<1 41
>1 yr%
0.629
Prob
abili
ty o
f Rem
aini
ng
With
out P
rogr
essi
on1.0
.8
.6
.4
.2
.00 18012060
HR D-Score >1 vs. 0-1= 28HR D-Score >1 vs <0 = 72
D-Score>1
D-Score 0-1
D-Score <0
Cancer Outcomesin 477 “Hyperplasias” restratified by EIN
Follow-up Time (> 12 mo)From Baak, Mutter, Robboy et al, Cancer June 2005
EIN
Proliferative
31%
ComplexAtypical
SimpleNon-Atypical
ComplexNon-Atypical
Endometrial Intraepithelial Neoplasia
52% 43%
20%
Baak et al 2005
SimpleAtypical
36%
N=56 N=67 N=65 N=188
25%
25% 19%
EIN No EIN
2 of every 3 “hyperplasia” casesare benign
EIN: ICD-9EIN: ICD-9As of January 1, 2010
621.34Benign endometrial hyperplasia
621.35Endometrial 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%
PathologistStyle Group
Cas
e
2028362940376418273009210431604863170816323819141526113954620323614425065145072246422458565249433312050110134147505357595535
T S R N H J D K B I C G O P Q M E FALGREEN YELLOW RED
ExpertConcensus
Benign, non-EINEINCancer
Diagnosis
No Data
Usubutun et al, 2012
Community: "Expert"EIN Diagnostic Reproducibility
ExpertConsensuskappa=0.74Community-Expert:20 pathologists79% agree w expert. Community to expert kappas= 0.72 (.45-.84)
Discordant CasesDefines Pathologist Style
Ref Dx Red Green ExplanationOverDx UnderDx
EIN EIN B9 Small focus, EIN in anovPolyp; Loose, Subtle
B9 EIN B9 Fragment, Shattered, Thick
PTEN & mutationsPTEN & mutations
PAX2 (10q24)PAX2 (10q24)
• Transcription factor• Embryonic expression required for:
KidneyMesonephric structuresParamesonephric 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
normalbackground
*
+
*
+
*
+
*
+
* *
+
+
08-111
Coinactivated PAX2 & PTEN in EIN
Mutter, 2010
PAX2 & PTEN null ratesby dx
Mutter, 2010
PE (normal)
EIN Cancer
PAX2 null 36% 71% 77%PTEN null 49% 44% 68%Both express 36% 15% 10%
Atypical Hyperplasiakappa=0.34-0.47
= EINkappa=0.54-0.62
TruePrecancer
TargetInterobserver ReproducibilityImproved
WHO-2014 (New) Endometrial Hyperplasia
System
WHO-2014 (New) Endometrial Hyperplasia
SystemBenign
Hyperplasia without atypicaPrecancer
Atypical hyperplasia / Endometrioid Intraepithelial Hyperplasia
AcknowledgementsAcknowledgements• Jan Baak, MD, Professor of Pathology
Stavanger University Hospital, NorwayUniversity of Munich, Germany
• George Mutter, MD, Professor of PathologyBrigham & Womens’ HospitalHarvard University Medical SchoolAlso see www.endometrium.org
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