Current C Current C Current C Current C Concepts of Concepts of - - PowerPoint PPT Presentation

Current C Current C Current C Current C Endometri Endometri Endometri Endometri Classif Classif

George L. Mutter George L. Mutter Harvard Medical Harvard Medical Brigham and Wo Brigham and Wo Boston, MA Boston, MA

Concepts of Concepts of Concepts of Concepts of ial Cancer ial Cancer ial Cancer ial Cancer fication fication

r, MD r, MD l School and l School and

• men’s Hospital
• men’s Hospital

Endometr

Type I Type I Endometrioid Endometrioid

ial Cancer

Type II Type II Non Non-

• Endometrioid

Endometrioid

Endometrial Carcin Endometrial Carcin

1970’s 1970’s

• Adenocarcinoma

Adenocarcinoma (NOS) (NOS)

• Adenoacanthoma

denoacanthoma -

• adenosquamous CA

adenosquamous CA

• Mesonephroid

esonephroid carcinoma carcinoma

noma Classification noma Classification

2014, WHO 2014, WHO

• Endometrioid carcinoma
• Mucinous carcinoma

Mucinous carcinoma

• Serous carcinoma
• Clear cell carcinoma
• Carcinosarcoma
• Neuroendocrine tumours
• Mixed carcinomas
• Undifferentiated carcinoma

Endometrioid

Mazelike/Rambling Villogla

d Carcinoma

andular Cribriform/Solid

early 1980’s early 1980’s Serous s Serous Carcinoma Carcinoma

Age at Diagnosis Wi Age at Diagnosis Wi

20

ge at ag os s ge at ag os s

n mean me EMOID 108 61 2

15 t

Non-EMOID 23 67.2 EMOID 108 61.2

10 Count 5 30 40 50 A A

ith Endometrial Cancer ith Endometrial Cancer t do et a Ca ce t do et a Ca ce

edian 62 5 67.8 62.5

60 70 80 90 AGE AGE

Mutter, 2005

Endometrial Cancer Endometrial Cancer

Histologic g Type Endometrioid Ad i Adenocarcinoma Grade 1 Grade 2 G d 3 Grade 3 Papillary Serous

r Treatment Failures r Treatment Failures

Treatment Failure % 2.3 5.4 43 6 43.6 62.5

Burke et. al. Obstet. Gynecol. 1990

Pap Ser (P53) Pap Ser (P53)

PTEN loss: Type I Pathway Endometrioid Carcinoma Endometrioid Carcinoma EIN EIN P53 mutation: Type II Pathway Papillary Serous Carcinoma Papillary Serous Carcinoma Serous EIC Serous EIC

Differences

Feature Endo

Endometria

Feature Endo p53 mutation 5- PTEN inactivation 5 endom muc Histotype muc sec squ Grades Behavior Ind Risk factors hor

s in Type I/II

metrioid Non-

l Carcinomas

metrioid Endometrioid

• 10%

80-90% 55% 11% metrioid, cinous cinous, cretory, amous papillary serous I-III not applicable dolent Aggressive rmonal not significant

Cl C ll C Cl C ll C Clear Cell C Clear Cell C i C i Carcinoma Carcinoma

Carcinos Carcinos C sarcoma sarcoma

Carcinos Carcinos C sarcoma sarcoma

? ? ? ? ? ? ? ?

Carcino Carcino

? ? ? ? ? ? ? ?

• sarcoma
• sarcoma

Risk Risk F Risk Risk F

E d t Endometr Carcinom HR HR Weight >200 lb 4.8 Exogenous E2 2.0 Nulliparous 2.9 OCP use 0.39 Smoking current 0 34 Smoking current 0.34 n 378

actors actors actors actors

i id rioid ma Carcinosarcoma HR HR 3.2 1.8 1.7 0.76 0 57 0.57 26

(Zelmanowicz, 1998) (Zelmanowicz, 1998)

WHO Blue Book MMM MMM

“It immuno molecu carcin carcin compon featu “Should li cli

MT MT → Carcinosarcoma → Carcinosarcoma

t should be noted that clinical,

• histochemical, ultrastructural, and

ular studies have all suggested that gg nosarcomas are really metaplastic nomas in which the mesenchymal nent retains at least some epithelial res in the vast majority of cases.” d not be grouped histogenetically or i ll ith t i ” nically with uterine sarcomas”

Mutter and Prat, 2014 Mutter and Prat, 2014

One Tumor, O One Tumor, One Diagnosis One Diagnosis

Intratumor H Intratumor Heterogeneity eterogeneity

Mutter, 2000 Mutter, 2000

The tu The tu is n is n is n is n the who the who the who the who umor umor not not not not

• le story
• le story
• le story
• le story

my my LVI LVI yoinvasion yoinvasion

Host Response Host Response

Broad Front Broad Front

Blunt without response Blunt without response

to to Myoinvasion Myoinvasion

microcystic, elongated or fragmented (MELF) microcystic, elongated or fragmented (MELF)

D R D R

• Dx. Repro
• Dx. Repro

Expert A vs Expert A vs

kappa score 0 kappa score 0-

• 1

1

d ibilit d ibilit

• ducibility
• ducibility
• s. Expert B
• s. Expert B

Pathologists are creatures o Pathologists are creatures of experience and belief

• f experience and belief

WHO Endometrial Diag

70 A. B. 30 40 70 60 50 Frequency 10 20 40 C. D. 10 20 30 10 Frequen 10 20 30 40 l l l l l cy l benign sh ch ah ca l l l l l Diagnosis benign l

SH, Simple Hyperplasia CH, Complex Hyperplasia AH, Atypical Hyperplasia CA, Carcinoma

noses, 4 Pathologists

l l l l n sh ch ah ca l l l l Diagnosis Mutter, Crum, Richart, Ferenczy, 2000

20 Pathologists (column) 20 Pathologists (column) 2 “Experts” (pullout col) 2 “Experts” (pullout col)

Di i

p (p ) p (p ) 63 Cases (rows) 63 Cases (rows)

C

Benign, non-EIN EIN Cancer Diagnosis g , No Data

Community-Expert: 79% of Dx agree with expert. Community to expert kappas average 0.72 (range 0 45-0 84)

Usubutun et al, 2012

(range 0.45-0.84)

Case

T S R N H J D K B I C G O P Q M E FAL GREEN GREEN YELLOW YELLOW RED RED Expert Expert Concensus Concensus

Pathol Pathol Pathol Pathol

• Inter

Inter-

• Observer

Observer Variatio Variatio

• Dx Repertoire is a per

Dx Repertoire is a per “Lumpers vs. “Splitter “Lumpers vs. “Splitter

• Can be either Benign o

Can be either Benign o

• gists
• gists
• gists
• gists
• n is Nonrandom
• n is Nonrandom

rsonal belief system rsonal belief system rs” rs”

• r Malignant
• r Malignant

Tumor Classifica Tumor Classifica

Hormonal Hormonal Sporadic Sporadic Germlin Germlin

SK SK

EIN EIN serous E serous E

Sporadic Sporadic Germlin Germlin

RI RI

Endometrioid Endometrioid Serous Serous Clear Ce Clear Ce

I II II

ENOTYPE ENOTYPE

None None MELF (EM MELF (EM

PI3K PI3K– –AKT AKT– –mTOR mTOR p53 p53 MAPK (KRA MAPK (KRA

PHE PHE LAR LAR

POLE (Ultramutated) POLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) C Marker Marker -

• DrugA

DrugA Marker Marker -

• DrugB

DrugB Marker Marker -

• Dru

Dru

MOLECUL MOLECUL

ation Parameters ation Parameters

Non Non-

• Hormonal

Hormonal ne ne Unknown Unknown

Nongenetic G ti

EIC EIC none none

ne ne Unknown Unknown

Genetic Precursor

ll ll Carcinosarcoma Carcinosarcoma Other Other

III III IV IV

Histotype Stage

MT) MT) Inflammatory Inflammatory

AS) AS) Wnt (b Wnt (b-

• catenin)

catenin) ErbB2 (Her2) ErbB2 (Her2)

Host Resp Pathway

Copy number Low Copy number Low Copy Number High Copy Number High ugC ugC Marker Marker -

• DrugD

DrugD Marker Marker -

• DrugE

DrugE

Stability Rx Marker

Tumor Classifica Tumor Classifica

Hormonal Hormonal Sporadic Sporadic Germlin Germlin

SK SK

EIN EIN serous E serous E

Sporadic Sporadic Germlin Germlin

RI RI

Endometrioid Endometrioid Serous Serous Clear Ce Clear Ce

I II II

ENOTYPE ENOTYPE

None None MELF (EM MELF (EM

PI3K PI3K– –AKT AKT– –mTOR mTOR p53 p53 MAPK (KRA MAPK (KRA

PHE PHE LAR LAR

POLE (Ultramutated) POLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) C Marker Marker -

• DrugA

DrugA Marker Marker -

• DrugB

DrugB Marker Marker -

• Dru

Dru

MOLECUL MOLECUL

ation Parameters ation Parameters

Non Non-

• Hormonal

Hormonal ne ne Unknown Unknown

Nongenetic G ti

EIC EIC none none

ne ne Unknown Unknown

Genetic Precursor

ll ll Carcinosarcoma Carcinosarcoma Other Other

III III IV IV

Histotype Stage

MT) MT) Inflammatory Inflammatory

AS) AS) Wnt (b Wnt (b-

• catenin)

catenin) ErbB2 (Her2) ErbB2 (Her2)

Host Resp Pathway

Copy number Low Copy number Low Copy Number High Copy Number High ugC ugC Marker Marker -

• DrugD

DrugD Marker Marker -

• DrugE

DrugE

Stability Rx Marker

Hormo Hormo S di S di G li G li

SK SK

EIN EIN

Sporadic Sporadic Germlin Germlin

RI RI

Endometrio Endometrio

I II II

ENOTYPE ENOTYPE

MELF (EMT) MELF (EMT) Inflammat Inflammat

PI3K PI3K– –AKT AKT–

PHE PHE LAR LAR

OLE (Ultramutated) OLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) Copy numb Copy numb DrugA DrugA Marker Marker -

• DrugB

DrugB Marker Marker -

• DrugC

DrugC Marker Marker -

• D

MOLECUL MOLECUL

• nal
• nal

Non Non-

• Hormonal

Hormonal U k U k

serous EIC serous EIC n n

ne ne Unknown Unknown

• id
• id

Serous Serous Clear Cell Clear Cell Carcinosarco Carcinosarco

III III IV IV

tory tory

–mTOR mTOR p53 p53 MAPK (KRAS) MAPK (KRAS) Wnt (b Wnt (b-

• cat

cat ber Low ber Low Copy Number High Copy Number High DrugD DrugD Marker Marker -

• DrugE

DrugE

Endometr Endometr Cl if Cl if Classif Classif

George L. Mutter George L. Mutter Harvard Medical Harvard Medical Brigham and Wo Brigham and Wo Boston, MA Boston, MA

rial Cancer rial Cancer fi ti fi ti fication fication

r, MD r, MD l School and l School and

• men’s Hospital
• men’s Hospital