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 Types: Endometrial Cancers Feature Histotype Behavior Risk factors Precursor Endometrioid Endometrioid, Secretory, Squamous Indolent Hormonal “Hyperplasia” NonEndometrioid Serous, Clear cell, Carcinosarcoma Aggressive None Serous EIC 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 • • • • 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 Criteria Glandular complexity Nuclear atypicality 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 WHO94 Endometrial Hyperplasia System C Y T O L O G Y No atypia→ Atypia → Simple Complex Simple Complex 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 Community cases submitted as atypical hyperplasia Trimble, Gyn Onc 2004 40% Benign/Hyper 30% Atyp Hyper 30% Cancer Problems in diagnosis: GOG experience Expert gynecologic pathologists disagree among themselves 60% disagreement Zaino, USCAP 2004 EIN: Endometrial Intraepithelial Neoplasia Conceptual shift in thinking EIN – Conceptual Import • Genetic changes key, not estrogen • Computer measurable (Reproducible) • Weeds out cases that otherwise might likely be treated • May identify latent cases Monoclonal 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 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 + 0.0439 x (Volume % Stroma) – 0.1592 x (Outer Surface Density glands) – 3.9934 x Ln (Std Dev Shortest Nuclear Axis) + 0.6229 Progression risk: 40-60% 25-30% ~ 0% -4 +5 0 +1 Frequency: 15-25% Baak 1988 5% 65% Contribution to D-Score § Volume % Glands § Perimeter Basement Membr 65% 25% § Standard Deviation Shortest Nuclear Axis 10% ARCHITECTURAL FEATURES MORE IMPORTANT THAN CYTONUCLEAR FEATURES Volume Percentage Stroma OUTER SURFACE DENSITY GLANDS EIN Gland Normal Gland Hyperplasia Basal Membrane = Outer Surface Density Increases from Normal à Hyperplasia à EIN Clinical Outcome of 176 WHO “Hyperplasias” 100 Followup, Months 80 60 40 Outcome Cancer No Cancer 20 0 SH (3/95) CH (2/22) AH (18/59) Mutter, 2002 Clinical Outcome of 176 “Hyperplasias” Rediagnosed by EIN Criteria 100 Followup, Months 80 60 40 20 Outcome Cancer No Cancer No EIN (1/111) EIN (22/65) Mutter 2002 Timing - a critical flaw Concurrent Appears in 1st year Progression Appears in 2nd or later years Concept 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 94 <1 yr SH CH SAH CAH % >1 yr % 4 9 20 53 0.7 9 7 20 Progression – EIN D-score <1 yr Score % >1 yr % 0 41 0.6 29 >1 <1 Cancer Outcomes in 477 “Hyperplasias” restratified by EIN Probability of Remaining Without Progression 1.0 D-Score>1 .8 D-Score 0-1 .6 D-Score <0 .4 HR D-Score >1 vs. 0-1= 28 .2 .0 0 HR D-Score >1 vs <0 = 72 60 120 180 Follow-up Time (> 12 mo) From Baak, Mutter, Robboy et al, Cancer June 2005 Proliferative EIN Complex Atypical Simple Atypical N=56 Complex Non-Atypical N=67 52% N=65 43% 25% 25% Simple Non-Atypical N=188 36% 19% 31% Endometrial Intraepithelial Neoplasia 20% Baak et al 2005 EIN No EIN 2 of every 3 “hyperplasia” cases are benign EIN: 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 70% Yes Community: "Expert" EIN Diagnostic Reproducibility Case Expert Consensus kappa=0.74 Community-Expert: 20 pathologists 79% agree w expert. Community to expert kappas= 0.72 (.45-.84) Pathologist Style Group 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 Diagnosis Cancer EIN Benign, non-EIN No Data T S R N H J D K B I C G O P Q M E FAL Expert Concensus GREEN YELLOW RED Usubutun et al, 2012 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 & mutations 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, 199 EIN: EIN: 08-111 H&E PTEN EIN: PAX2 Coinactivated PAX2 & PTEN in EIN H&E PTEN PAX2 normal background + + * + * * * * + + * + EIN 08-111 Mutter, 2010 PAX2 & PTEN null rates by dx PE (normal) PAX2 null 36% PTEN null 49% Both express 36% EIN Cancer 71% 44% 15% 77% 68% 10% Mutter, 2010 True Precancer = EIN kappa=0.54-0.62 Target Interobserver Reproducibility Improved Atypical Hyperplasia kappa=0.34-0.47 WHO-2014 (New) Endometrial Hyperplasia System Benign Hyperplasia without atypica Precancer Atypical hyperplasia / Endometrioid Intraepithelial Hyperplasia 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 www.endometrium.org
© Copyright 2024 ExpyDoc
