EIN. (Endometrial Intraepithelial Neoplasia): Improved Criteria for diagnosing endometrial precancer. Stanley J. Robboy, MD, FCAP,
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1 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
2 Types: Endometrial Cancers Feature Histotype Endometrioid Endometrioid, Secretory, Squamous Non- Endometrioid Serous, Clear cell, Carcinosarcoma Behavior Indolent Aggressive Risk factors Hormonal None Precursor Hyperplasia Serous EIC
3 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
4 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
5 WHO94 Endometrial Hyperplasia System Criteria Glandular complexity Nuclear atypicality
6 WHO94 Endometrial Hyperplasia System A R C H I T E C T U R E Simple Complex No atypia With atypia No atypia With atypia
7 WHO94 Endometrial Hyperplasia System C Y T O L O G Y No atypia Atypia Simple Complex Simple Complex
8 Progression to cancer Nested case control (2008) Hyperplasia Relative Risk Simple 2.0 Complex 2.8 Atypical 14.0 Lacey 2008
9 Problems in diagnosis: GOG experience Community cases submitted as atypical hyperplasia 40% Benign/Hyper 30% Atyp Hyper 30% Cancer Trimble, Gyn Onc 2004
10 Problems in diagnosis: GOG experience Expert gynecologic pathologists disagree among themselves 60% disagreement Zaino, USCAP 2004
11 EIN: Endometrial Intraepithelial Neoplasia Conceptual shift in thinking
12 EIN Conceptual Import Genetic changes key, not estrogen Computer measurable (Reproducible) Weeds out cases that otherwise might likely be treated May identify latent cases
13
14 Monoclonal Origin Point origin and expansile growth Select relevant fields Size changes over time Lesion contrasts with normal Compare internally
15 Ratio glands to stroma Volume % glands Length of basement membrane Outer surface density of glands Nuclear pleomorphism Std deviation of shortest nuclear diameter
16 EIN 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
17 x (Volume % Stroma) x (Outer Surface Density glands) x Ln (Std Dev Shortest Nuclear Axis) Progression risk: 40-60% 25-30% ~ 0% Frequency: 15-25% 5% 65% Baak 1988
18 Contribution to D-Score Volume % Glands 65% Perimeter Basement Membr 25% Standard Deviation Shortest Nuclear Axis 10% ARCHITECTURAL FEATURES MORE IMPORTANT THAN CYTONUCLEAR FEATURES
19 Volume Percentage Stroma
20 OUTER SURFACE DENSITY GLANDS EIN Gland Hyperplasia Normal Gland Basal Membrane = Outer Surface Density Increases from Normal Hyperplasia EIN
21 Clinical Outcome of 176 WHO Hyperplasias Followup, Months Outcome Cancer No Cancer 0 SH (3/95) CH (2/22) AH (18/59) Mutter, 2002
22 Clinical Outcome of 176 Hyperplasias Rediagnosed by EIN Criteria Followup, Months No EIN (1/111) EIN (22/65) Outcome Cancer No Cancer Mutter 2002
23 Timing - a critical flaw Concurrent Appears in 1 st year Progression Appears in 2 nd or later years
24 Concept of Progression Concurrent: Tumor appears in 1 st year, i.e., < 1 yr follow-up 197 women Progression: Appears > 1 year 477 women (median 48 mo, max 22 yrs)
25 Progression WHO 94 <1 yr % SH 4 CH 9 SAH 20 CAH 53 >1 yr %
26 Progression EIN D-score <1 yr Score % >1 0 <1 41 >1 yr %
27 Cancer Outcomes in 477 Hyperplasias restratified by EIN 1.0 D-Score>1 Probability of Remaining Without Progression HR D-Score >1 vs. 0-1= 28 HR D-Score >1 vs <0 = 72 D-Score 0-1 D-Score < Follow-up Time (> 12 mo) From Baak, Mutter, Robboy et al, Cancer June 2005
28
29 Proliferative EIN
30
31 Complex Atypical Simple Atypical Complex Non-Atypical Simple Non-Atypical N=56 N=67 N=65 N=188 52% 43% 36% 25% 19% 25% 31% Endometrial Intraepithelial Neoplasia 20% Baak et al 2005
32 EIN No EIN 2 of every 3 hyperplasia cases are benign
33 EIN: ICD-9 As of January 1, Benign endometrial hyperplasia Endometrial intraepithelial neoplasia [EIN]
34 EIN Reproducibility UsubutumA et al Modern Pathol 25: , 2012
35 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%
36 Community: "Expert" EIN Diagnostic Reproducibility Expert Consensus kappa=0.74 Community-Expert: 20 pathologists 79% agree w expert. Community to expert kappas= 0.72 ( ) Case Pathologist Style Group TSRNHJDKBICGOPQMEFAL GREEN YELLOW RED Expert Concensus Diagnosis Cancer EIN Benign, non-ein No Data Usubutun et al, 2012
37 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
38 PTEN & mutations
39 PAX2 (10q24) Transcription factor Embryonic expression required for: Kidney Mesonephric structures Paramesonephric ducts 5-fold reduced in endometrial Ca
40 PAX2 knockout leads to Mullerian and renal atresia Dressler, 199
41 EIN: PTEN H&E EIN: PAX
42 Coinactivated PAX2 & PTEN in EIN H&E PTEN PAX2 normal background * * * * * * EIN Mutter, 2010
43 PAX2 & PTEN null rates by dx PE (normal) EIN Cancer PAX2 null 36% 71% 77% PTEN null 49% 44% 68% Both express 36% 15% 10% Mutter, 2010
44 Interobserver Reproducibility Improved True Precancer Target = EIN kappa= Atypical Hyperplasia kappa=
45 WHO-2014 (New) Endometrial Hyperplasia System Benign Hyperplasia without atypica Precancer Atypical hyperplasia / Endometrioid Intraepithelial Hyperplasia
46 Acknowledgements 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
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