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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 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