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Current C Current C Current C Current C Concepts of Concepts of Concepts of Concepts of Endometri Endometri Endometri Endometri ial Cancer ial Cancer ial Cancer ial Cancer Classif Classif fication fication George L. Mutter George L. Mutter r, MD r, MD Harvard Medical Harvard Medical l School and l School and Brigham and Wo Brigham and Wo omen’s Hospital omen’s Hospital Boston, MA Boston, MA

Endometr ial Cancer Type I Type I Type II Type II Endometrioid Endometrioid Non Non- -Endometrioid Endometrioid

Endometrial Carcin Endometrial Carcin noma Classification noma Classification 1970’s 1970’s 2014, WHO 2014, WHO • Endometrioid carcinoma • Adenocarcinoma Adenocarcinoma (NOS) (NOS) • Mucinous carcinoma Mucinous carcinoma • Serous carcinoma • Adenoacanthoma denoacanthoma - - • Clear cell carcinoma • Carcinosarcoma adenosquamous CA adenosquamous CA • Neuroendocrine tumours • Mixed carcinomas • Mesonephroid esonephroid carcinoma carcinoma • Undifferentiated carcinoma

Endometrioid d Carcinoma Mazelike/Rambling Cribriform/Solid Villogla andular

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

Age at Diagnosis Wi Age at Diagnosis Wi ge at ge at ag os s ag os s ith Endometrial Cancer ith Endometrial Cancer t t do do et a Ca ce et a Ca ce 20 n mean me edian EMOID EMOID 108 108 61.2 61 2 62 5 62.5 Non-EMOID 23 67.2 67.8 15 Count t 10 5 0 30 40 50 60 70 80 90 A A AGE AGE Mutter, 2005

Endometrial Cancer Endometrial Cancer r Treatment Failures r Treatment Failures Histologic g Treatment Type Failure % Endometrioid Ad Adenocarcinoma i Grade 1 2.3 Grade 2 5.4 Grade 3 G d 3 43 6 43.6 Papillary Serous 62.5 Burke et. al. Obstet. Gynecol. 1990

Pap Ser (P53) Pap Ser (P53)

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

Differences s in Type I/II Endometria l Carcinomas Non- Feature Feature Endo Endo metrioid metrioid Endometrioid p53 mutation 5- -10% 80-90% PTEN inactivation 5 55% 11% endom metrioid, muc muc cinous cinous, Histotype papillary serous sec cretory, squ amous Grades I-III not applicable Behavior Ind dolent Aggressive Risk factors hor rmonal not significant

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

Carcinos Carcinos C sarcoma sarcoma

Carcinos Carcinos C sarcoma sarcoma

? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Carcino Carcino osarcoma osarcoma

Risk F Risk Risk Risk F actors actors actors actors E d Endometr t rioid i id Carcinom ma Carcinosarcoma HR HR HR HR Weight >200 lb 4.8 3.2 Exogenous E2 2.0 1.8 Nulliparous 2.9 1.7 OCP use 0.39 0.76 Smoking current Smoking current 0.34 0 34 0 57 0.57 n 378 26 (Zelmanowicz, 1998) (Zelmanowicz, 1998)

WHO Blue Book MMM MMM MT MT → Carcinosarcoma → Carcinosarcoma “It t should be noted that clinical, immuno ohistochemical, ultrastructural, and molecu ular studies have all suggested that gg carcin nosarcomas are really metaplastic carcin nomas in which the mesenchymal compon nent retains at least some epithelial featu res in the vast majority of cases.” “Should d not be grouped histogenetically or cli li nically with uterine sarcomas” i ll ith t i ”

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 umor umor is n is n is n is n not not not not the who the who the who the who ole story ole story ole story ole story

LVI LVI my my yoinvasion yoinvasion

Host Response Host Response to to Myoinvasion Myoinvasion Broad Front Broad Front microcystic, elongated or fragmented (MELF) microcystic, elongated or fragmented (MELF) Blunt without response Blunt without response

D D Dx. Repro Dx. Repro R R oducibility oducibility d d ibilit ibilit Expert A vs Expert A vs s. Expert B s. Expert B kappa score 0 kappa score 0- -1 1

Pathologists are creatures o Pathologists are creatures of experience and belief of experience and belief

WHO Endometrial Diag noses, 4 Pathologists A. B. 70 70 Frequency 60 50 40 30 20 10 0 C. D. 40 30 20 Frequen 10 0 0 10 10 cy 20 30 40 l l l l l l l l l l l l l l l l l l l l SH, Simple Hyperplasia n sh ah ca ca ch benign sh ch ah benign Diagnosis Diagnosis CH, Complex Hyperplasia AH, Atypical Hyperplasia CA, Carcinoma Mutter, Crum, Richart, Ferenczy, 2000

20 20 Pathologists (column) 20 Pathologists (column) 28 36 29 40 37 2 “Experts” (pullout col) 2 “Experts” (pullout col) p p (p (p ) ) 64 18 27 30 30 09 21 63 Cases (rows) 63 Cases (rows) 04 31 60 48 63 17 08 16 32 Di Diagnosis i 38 38 19 14 15 Cancer 26 Case 11 39 EIN 54 62 C 03 Benign, non-EIN g , 23 61 44 No Data 25 06 51 45 07 22 46 42 24 58 56 56 52 Community-Expert: 49 43 79% of Dx agree with expert. 33 12 05 Community to expert 01 10 kappas average 0.72 13 41 47 (range 0.45-0.84) (range 0 45-0 84) 50 50 53 57 59 55 35 T S R N H J D K B I C G O P Q M E FAL Expert Expert Usubutun et al, 2012 Concensus Concensus GREEN GREEN YELLOW YELLOW RED RED

Pathol Pathol Pathol Pathol ogists ogists ogists ogists • Inter Inter- -Observer Observer Variatio Variatio on is Nonrandom on is Nonrandom • Dx Repertoire is a per Dx Repertoire is a per rsonal belief system rsonal belief system “Lumpers vs. “Splitter “Lumpers vs. “Splitter rs” rs” • Can be either Benign o Can be either Benign o or Malignant or Malignant

Tumor Classifica Tumor Classifica ation Parameters ation Parameters Hormonal Hormonal Non- Non -Hormonal Hormonal Nongenetic SK SK Sporadic Sporadic Sporadic Sporadic Germlin Germlin Germlin Germlin ne ne ne ne Unknown Unknown Unknown Unknown Genetic G ti RI RI EIN EIN serous E serous E EIC EIC none none Precursor Endometrioid Endometrioid Serous Serous Clear Ce Clear Ce ll ll Carcinosarcoma Carcinosarcoma Other Other Histotype ENOTYPE ENOTYPE I II II III III IV IV Stage PHE PHE None None MELF (EM MELF (EM MT) MT) Inflammatory Inflammatory Host Resp LAR LAR PI3K– PI3K –AKT AKT– –mTOR mTOR p53 p53 MAPK (KRA MAPK (KRA AS) AS) Wnt (b- Wnt (b -catenin) catenin) ErbB2 (Her2) ErbB2 (Her2) Pathway MOLECUL MOLECUL POLE (Ultramutated) POLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) Copy number Low Copy number Low C Copy Number High Copy Number High Stability Marker - Marker - DrugA DrugA Marker - Marker - DrugB DrugB Marker - Marker - Dru Dru ugC ugC Marker - Marker - DrugD DrugD Marker Marker - - DrugE DrugE Rx Marker

Tumor Classifica Tumor Classifica ation Parameters ation Parameters Hormonal Hormonal Non- Non -Hormonal Hormonal Nongenetic SK SK Sporadic Sporadic Sporadic Sporadic Germlin Germlin Germlin Germlin ne ne ne ne Unknown Unknown Unknown Unknown Genetic G ti RI RI EIN EIN serous E serous E EIC EIC none none Precursor Endometrioid Endometrioid Serous Serous Clear Ce Clear Ce ll ll Carcinosarcoma Carcinosarcoma Other Other Histotype ENOTYPE ENOTYPE I II II III III IV IV Stage PHE PHE None None MELF (EM MELF (EM MT) MT) Inflammatory Inflammatory Host Resp LAR LAR PI3K– PI3K –AKT AKT– –mTOR mTOR p53 p53 MAPK (KRA MAPK (KRA AS) AS) Wnt (b- Wnt (b -catenin) catenin) ErbB2 (Her2) ErbB2 (Her2) Pathway MOLECUL MOLECUL POLE (Ultramutated) POLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) Copy number Low Copy number Low C Copy Number High Copy Number High Stability Marker - Marker - DrugA DrugA Marker - Marker - DrugB DrugB Marker - Marker - Dru Dru ugC ugC Marker - Marker - DrugD DrugD Marker Marker - - DrugE DrugE Rx Marker

Hormo Hormo onal onal Non- Non -Hormonal Hormonal SK SK Sporadic S Sporadic S di di Germlin Germlin G G li li ne ne U k Unknown U k Unknown RI RI EIN EIN serous EIC serous EIC n n Endometrio Endometrio oid oid Serous Serous Clear Cell Clear Cell Carcinosarco Carcinosarco ENOTYPE ENOTYPE I II II III III IV IV PHE PHE MELF (EMT) MELF (EMT) Inflammat Inflammat tory tory PI3K PI3K– –AKT AKT– –mTOR mTOR p53 p53 MAPK (KRAS) MAPK (KRAS) Wnt (b- Wnt (b -cat cat LAR LAR MOLECUL MOLECUL OLE (Ultramutated) OLE (Ultramutated) MSI (Hypermutated) MSI (Hypermutated) Copy numb Copy numb ber Low ber Low Copy Number High Copy Number High DrugA DrugA Marker - Marker - DrugB DrugB Marker - Marker - DrugC DrugC Marker Marker - - D DrugD DrugD Marker Marker - - DrugE DrugE