PATOLOGIA MOLECULAR DEL CANCER GINECOLOGICO. Xavier Matias-Guiu Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA.

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1 PATOLOGIA MOLECULAR DEL CANCER GINECOLOGICO Xavier Matias-Guiu Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA.

2 Carcinoma de Endometrio Cáncer de Ovario

3 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma, usual/variants 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell Carcinoma 5- Neuroendocrine tumors 6- Mixed carcinoma 7- Undifferentiated carcinoma Carcinosarcoma WHO 2014

4 The 2 types of Endometrial Carcinoma Type I Type II Age Pre- and Perimenop Postmenopausal Unopposed Estrogen Present Absent Hyperplasia-Precursor Present Absent Grade Low High Myometrial Invasion Minimal Deep Histologic Type Endometrioid Nonendometrioid Behavior Stable Progressive Modif from Bokhman JV, Gynecol Oncol 1983

5 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell carcinoma Type I Type II 6- Mixed carcinoma 7-Undifferentiated carcinoma Carcinosarcoma (MMMT) Mixed Tumors

6 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma, usual/variants 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell Carcinoma 5- Neuroendocrine tumors 6- Mixed carcinoma 7- Undifferentiated carcinoma Type I Carcinosarcoma WHO 2014

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9 Endometrioid Carcinoma Genetic Alterations PIK3CA 30% PTEN 30-60% Microsatellite Instability 20-30% FGFR % K-ras 10-30% ARID 1A 30% Beta-catenin 28-35%

10 Endometrioid Carcinoma Genetic Alterations PIK3CA 30% PTEN 30-60% Microsatellite Instability 20-30% FGFR % K-ras 10-30% Beta-catenin 28-35%

11 P PIP 2 Dephosphorylation ATP PTEN PI3K Phosphorylation ADP PIP 3 AKT-P Cell Proliferation and Survival

12 PTEN mutations in Endometrial Ca (Clinical Relevance) Endometrioid Ca Activation of PIK3 pathway, but also promotes genomic, instability Early event. Null-glands in 50% normal woman

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15 PI3K signalling pathway mutations in endometrial carcinoma PTEN PIK3CA p110α PIK3R1 p85 α AKT1 AKT2 AKT % EEC 25-50% EEC; 30% NEEC 43% EEC; 12% NEEC 2% EC 7% EC 2% EC

16 PIK3CA mutations in Endometrial Ca Endometrioid Ca (20 36%), but also in serous ca. Uncommon in Endometrial Hyperplasia Possible additive effect with monoallelic PTEN alteration Myometrial and vascular invasion Activation PIK3 pathway

17 Endometrioid Carcinoma Genetic Alterations PIK3CA 30% PTEN 30-60% Microsatellite Instability 20-30% FGFR % K-ras 10-30% Beta-catenin 28-35%

18 FGF FGFR 2 16 % FRS2 Grb2 Shp2 SOS Grb2 Ras 19 % Raf MEK RASF1A 70 % Sprouty 20 % Erk

19 Endometrioid Carcinoma Genetic Alterations PIK3CA 30% PTEN 30-60% Microsatellite Instability 20-30% FGFR % K-ras 10-30% Beta-catenin 28-35%

20 Beta-Catenin Mutations in Endometrial Cancer Endometrioid Ca (14 44%) More frequent in early stages? Good prognostic marker? S37C

21 Endometrioid Carcinoma Genetic Alterations PIK3CA 30% PTEN 30-60% Microsatellite Instability 20-30% FGFR % K-ras 10-30% Beta-catenin 28-35%

22 Microsatellite Instability (Sporadic Tumors) PRO MLH1 Active Gene Random Methylation Errors PRO MLH1 Reduced Expression Clonal Selection of Cells Further Random Methylation Errors PRO MLH1 Silenced Gene

23 ATGCTCTAGTATCTAGCTCGTACGT ATCGTAAAAAAAAAATGCATCATG TGAGCACACACACACACACATGCTAG MICROSATELLITES

24 Microsatellite Instability D5S107 D10S197 D12S79 D12S95 D18S58 N T N T N T N T N T

25 C H T T1 T2 T3 BAT-25 RAD50 (A) 9 N T T N MLH-1 T+N T+N

26 T1 T2 T1 T2 BAX

27 Microsatellite Instability in Endometrial Ca (Clinical Relevance) Endometrioid Ca (20 35%) Familial or Sporadic Mismatch DNA repair alteration High grade and poor prognosis in some series. Favourable outcome or similar overall survival in other series Early stages

28 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell carcinoma Type I Type II 6- Mixed carcinoma 7-Undifferentiated carcinoma Carcinosarcoma (MMMT) Mixed Tumors

29 Serous carcinoma Accounts for 5 10% endometrial ca. Prototype of type II ca Very aggressive May be associated with multicentricity (endocervix, fallopian tube), extensive peritoneal spread and pleural metastases. Thick papillae with highly atypical cells. Extensive lymph vessel invasion

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31 The 2 types of Endometrial Carcinoma Endometrioid Non-Endometrioid Genetic alterations Microsat Instability p53, PTEN, LOH KRAS, p16 beta-catenin (CTNNB1) E-cadherin FGFR2 c-erb B2 STK15 PIK3CA PIK3CA ARID1A ARID1A

32 Non-Endometrioid Carcinoma Genetic Alterations C-erbB2 26% p16 40% Cyclins 26-42% E-cadherin 90% p53 90%

33 P53 alterations 90% Widespread LOH N T CDH1 LOH (57%) N Reduced E-cadherin 87% T D16S496 C-erbB2 amplification 30% Cyclin D1 (26%) and Cyclin E (42%) amplification Cyclin D1 CCND1 Cyclin E CCNE

34 The 2 types of Endometrial Carcinoma Type I Type II Microsat Instability 20-40% 0 5% PTEN 35-50% 10% KRAS 15-30% 0-5% beta-catenin (CTNNB1) 25-40% 0-5% p % 90% P16 10% 40% E-cadherin 10-20% 80-90% c-erb B2 2.5% 26% Cyclins D1 and E 2-5% 26-42% STK15

35 Grade 3 EEC Clear Cell Grade 1 and 2 EEC Serous Mixed End-Nonend Ambiguous Endometrioid Non-Endometrioid

36 Endometrial carcinoma TCGA, 2013

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38 Grade 3 EEC Clear Cell Grade 1 and 2 EEC Serous Mixed End-Nonend Ambiguous Endometrioid Non-Endometrioid

39 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell carcinoma Type I Type II 6- Mixed carcinoma 7-Undifferentiated carcinoma Carcinosarcoma (MMMT) Mixed Tumors

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41 p53

42 EEC in mixed Pure EEC NEEC in mixed Pure NEEC KRAS 14.7% 17.0% 17.9% 8.6% PTEN 11.8 % 19.6% 7.1% 2.9% p53 8.8% 1.7% 14.3% 17.1% PIK3CA 26.5% 13.5% 25.0% 14.3%

43 Endometrial carcinoma (Histological Classification) 1- Endometrioid carcinoma 2- Mucinous adenocarcinoma 3- Serous carcinoma 4- Clear cell carcinoma Type I Type II 6- Mixed carcinoma 7-Undifferentiated carcinoma Carcinosarcoma (MMMT) Mixed Tumors

44 Carcinoma de Endometrio Cáncer de Ovario

45 TUMORES DEL EPITELIO- ESTROMA DEL OVARIO Serosos. Origen en el epitelio de la Trompa Mucinosos?? Endometrioides. Origen en Endometriosis Célula Clara. Origen en Endometriosis Sero-mucinosos. Origen en Endometriosis Transicionales?? Indiferenciados?? Mixtos??

46 TUMORES DE OVARIO DE TIPO EPITELIO-ESTROMA Benignos (Cistoadenoma) Borderline Malignos (Carcinoma)

47 TUMORES DEL EPITELIO-ESTROMA DEL OVARIO MALIGNOS- CISTOADENOCARCINOMAS Ca Serosos de AltoGrado 70% Ca Serosos de Bajo grado 5% Ca Endometrioides 10% CA Célula Clara 10% Ca Mucinosos 3%

48 CARCINOMA SEROSO DE ALTO GRADO

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50 High grade ovarian serous carcinoma Sporadic Familial (BRCA-1; BRCA-2)

51 Normal Ovary or Tube P53, BRCA-1, BRCA-2, Rb-1 High grade Serous Ca

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55 Normal Ovary or Tube P53, BRCA-1, BRCA-2, Rb-1 High grade Serous Ca

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63 TUMORES DEL EPITELIO-ESTROMA DEL OVARIO MALIGNOS- CISTOADENOCARCINOMAS Ca Serosos de AltoGrado 70% Ca Serosos de Bajo grado 5% Ca Endometrioides 10% CA Célula Clara 10% Ca Mucinosos 3%

64 CARCINOMA SEROSO DE BAJO GRADO

65 Normal Ovary or tube BRAF, k-ras Serous Borderline Low grade Serous Ca Normal Ovary or Tube P53, BRCA-1, BRCA-2, Rb-1 High grade Serous Ca

66 TUMORES DEL EPITELIO-ESTROMA DEL OVARIO MALIGNOS- CISTOADENOCARCINOMAS Ca Serosos de AltoGrado 70% Ca Serosos de Bajo grado 5% Ca Endometrioides 10% CA Célula Clara 10% Ca Mucinosos 3%

67 MOLECULAR FEATURES OF ENDOMETRIOID CARCINOMA ENDOMETRIUM OVARY

68 MUTACIÓN DE b-catenina EN CARCINOMA ENDOMETRIOIDE DE OVARIO Ser(TCT)33(TGT)Cys

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70 TUMORES DEL EPITELIO-ESTROMA DEL OVARIO MALIGNOS- CISTOADENOCARCINOMAS Ca Serosos de Bajo Grado 5% Ca Serosos de Alto grado 70% Ca Endometrioides 10% CA Célula Clara 10% Ca Mucinosos 3%

71 CARCINOMAS MUCINOSOS DEL OVARIO Raros (2.4% de carcinomas ovaricos) Unilaterales Frecuentemente coexisten con componente benigno o borderline Descartar metástasis de cáncer de colon, apéndice, páncreas o via biliar.

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74 Cuatrecasas M, Matias-Guiu X, Prat J. Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-ki-ras mutations. Am J Surg Pathol :739-46

75 Simultaneous endometrioid carcinomas of the endometrium and the ovaries

76 Simultaneous endometrioid carcinomas of the endometrium and the ovaries (Criteria) Tumor sizes Histological grades Bilaterality Pattern of tumor growth Tubal, myometrial, vascular invasion Presence of endometriosis

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78 MOLECULAR FEATURES OF ENDOMETRIOID CARCINOMA ENDOMETRIUM OVARY

79 Independent Primary Endometrioid Carcinomas of Uterus and Ovary Different MI pattern Irving J et al Hum Pathol 2005

80 Metastatic Carcinoma (Identical MI pattern - AWT at 3 y) Irving J et al Hum Pathol 2005

81 Independent carcinomas 18 yrs

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84 PTEN null PTEN wt PTEN null PTEN wt

85 Simultaneous endometrioid carcinomas of the endometrium and the ovaries Independent tumors may occasionally show similar genetic alterations as their common precursor stem cells may carry such alterations.

86 PATOLOGIA MOLECULAR DEL CANCER GINECOLOGICO Xavier Matias-Guiu Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA.