Download - (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Transcript
Page 1: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 2: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Feature Endometrioid Non-Endometrioid

HistotypeEndometrioid,

Secretory, Squamous

Serous, Clear cell,

CarcinosarcomaBehavior Indolent Aggressive

Risk factors Hormonal NonePrecursor “Hyperplasia” Serous EIC

Types: Endometrial Cancers

Page 3: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 4: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 5: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

WHO94 Endometrial Hyperplasia SystemWHO94 Endometrial Hyperplasia System

CriteriaGlandular complexity

Nuclear atypicality

Page 6: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

WHO94 Endometrial Hyperplasia SystemWHO94 Endometrial Hyperplasia System

Simple →

Complex →

ARCHITECTURE

No atypiaWith atypia

No atypiaWith atypia

Page 7: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

WHO94 Endometrial Hyperplasia SystemWHO94 Endometrial Hyperplasia System

No atypia→

Atypia →

CYTOLOGY

SimpleComplex

SimpleComplex

Page 8: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 9: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 10: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Problems in diagnosis:GOG experience

Problems in diagnosis:GOG experience

Expert gynecologic pathologists

disagree among

themselves

60% disagreement

Zaino, USCAP 2004

Page 11: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

EIN: Endometrial Intraepithelial Neoplasia

EIN: Endometrial Intraepithelial Neoplasia

Conceptual shiftin thinking

Page 12: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 13: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,
Page 14: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Monoclonal OriginMonoclonal Origin• Point origin and expansile growth

Select relevant fieldsSize changes over time

• Lesion contrasts with normalCompare internally

Page 15: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

• Ratio glands to stroma– Volume % glands

• Length of basement membrane – ‘Outer surface density’ of glands

• Nuclear pleomorphism– Std deviation of shortest nuclear diameter

Page 16: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 17: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

+ 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

Page 18: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 19: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Volume Percentage Stroma

Page 20: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Normal GlandEIN Gland Hyperplasia

OUTER SURFACE DENSITY GLANDS

Basal Membrane = Outer Surface Density Increases from Normal à Hyperplasia à EIN

Page 21: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 22: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 23: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Timing - a critical flawTiming - a critical flawConcurrent

Appears in 1st year

ProgressionAppears in 2nd or later years

Page 24: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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)

Page 25: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Progression – WHO 94Progression – WHO 94<1 yr

%SH 4CH 9SAH 20CAH 53

>1 yr%

0.797

20

Page 26: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Progression – EIN D-scoreProgression – EIN D-score<1 yr

Score %>1 0<1 41

>1 yr%

0.629

Page 27: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 28: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,
Page 29: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

EIN

Proliferative

Page 30: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,
Page 31: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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%

Page 32: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

EIN No EIN

2 of every 3 “hyperplasia” casesare benign

Page 33: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

EIN: ICD-9EIN: ICD-9As of January 1, 2010

621.34Benign endometrial hyperplasia

621.35Endometrial intraepithelial neoplasia [EIN]

Page 34: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

EIN Reproducibility

Usubutum A et al

Modern Pathol 25: 877-884, 2012

Page 35: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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%

Page 36: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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)

Page 37: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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

Page 38: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

PTEN & mutationsPTEN & mutations

Page 39: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

PAX2 (10q24)PAX2 (10q24)

• Transcription factor• Embryonic expression required for:

KidneyMesonephric structuresParamesonephric ducts

• 5-fold reduced in endometrial Ca

Page 40: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

PAX2 knockout leads to Mullerian and renal atresia

Dressler, 1995

Page 41: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

08-111EIN: H&EEIN: PTENEIN: PAX2

Page 42: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

H&E PTEN PAX2

EIN

normalbackground

*

+

*

+

*

+

*

+

* *

+

+

08-111

Coinactivated PAX2 & PTEN in EIN

Mutter, 2010

Page 43: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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%

Page 44: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

Atypical Hyperplasiakappa=0.34-0.47

= EINkappa=0.54-0.62

TruePrecancer

TargetInterobserver ReproducibilityImproved

Page 45: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

WHO-2014 (New) Endometrial Hyperplasia

System

WHO-2014 (New) Endometrial Hyperplasia

SystemBenign

Hyperplasia without atypicaPrecancer

Atypical hyperplasia / Endometrioid Intraepithelial Hyperplasia

Page 46: (Endometrial Intraepithelial Neoplasia): Improved Criteria ... · Endometrial intraepithelial neoplasia [EIN] EIN Reproducibility UsubutumA et al Modern Pathol25: 877-884, 2012. Questionaire,

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