Patologia Molecular del Carcinoma de Ovario

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1 Curso de Patologia Molecular XXVI Congreso Nacional de la SEAP Cadiz Patologia Molecular del Carcinoma de Ovario Jaime Prat Barcelona

2 Ovarian Epithelial Tumors WHO 1999 and 2003 Serous Mucinous Endometrioid Clear cell Transitional Squamous Mixed Undifferentiated Benign 60% BL 10% Ca 30%

3 EPITHELIAL OVARIAN TUMORS A heterogeneous group Histologic type, Precursor lesions, Genetic alterations

4 Histologic Subtypes of Ovarian Carcinomas Serous high grade Serous low grade Clear cell Endometrioid Mucinous

5 New classification: Frequency HG serous LG serous Clear cell Endometrioid Mucinous Unclassifiable TP44

6 HGC LGSC MC EC CCC

7 These subtypes differ from each other with respect to: 1.Risk factors and precursor lesions 2.Patterns of spread 3.Molecular genetic alterations 4.Response to chemotherapy 5.Outcome

8 Biomarker profiles across subtypes Köbel M et al. PLoS Med 2008; 5:e232

9 Serous Carcinoma

10 HEREDITARY SUSCEPTIBILITY TO OVARIAN CANCER BRCA2 (30%) Lifetime risk 15-30% BRCA1 (65%) Lifetime risk 30-60% HNPCC (7%) Hereditary (10%) Sporadic (90%)

11 Piek et al. J Pathol 2001

12 Serous Intraepithelial Carcinoma STIC p53

13 How about less than STIC?

14 P53 signature Lee et al. J Pathol 2007

15 Crum C. 2012

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17 BRCA Promotes P53 Signature to TIC Normal P53 P53 signature BRCA1 TIC Hereditary : BRCA1 mutation constitutive Normal P53 P53 signature BRCA1 TIC Sporadic : BRCA1 methylation/mutation new event

18 Classification of Gyn Cancers based on Origin and Mutations? High-grade Serous Ca Fallopian Tube STIC TP53 BRCA1 Chromosomal instability Genetic chaos Endosalpingiosis

19 STIC P53 High Grade Serous Carcinoma

20 SBT in epithelial inclusion cyst

21 HGSC Pathogenetic Model DDL Bowtell Nature Rev Cancer 2010

22 Chromosomes from six ovarian cancers showing: chromosomal instability A B C X X D E X X F X X

23 Serous carcinoma, G3

24 Low grade High grade

25 SBT + MPSCa MPSCa

26 Serous Borderline Tumor

27 Peritoneal Implants (SBT) Non-invasive - Epithelial - Desmoplastic Invasive Bell DA, et al Cancer 1988; 62:2212 Noninvasive (desmoplastic) implant Noninvasive epithelial implant Invasive implant

28 Serous Tumors (Pathogenesis - Dualistic model) Bg SBT SBT-MP MP Ca (Inv) Low Gr Serous Ca KRAS and BRAF mutations (70%) High Grade Serous Ca p53 mutations, LOH 17q (80%) BRCA inactivation (80%) HER-2/neu amplification/overexpression Singer et al Am J Pathol 2002

29 Mucinous Tumors of the Ovary (From benign to malignant) 1960s 1970s Adenoma Borderline Carcinoma Ca 1980s 1990s Metastatic Ca Appendiceal t + PP Ca Ca

30 Mucinous Tumors (Ovary) Benign 75% Borderline 10% Carcinomas 15% 80% 17% 3% Koonings, 1998

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32 Mucinous glands Carcinoma Cystadenoma Borderline

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34 Epithelial Ovarian Tumors K-ras Mutations (12, 13) Benign Borderline Malignant (%) Mucinous (%) Non-Mucinous Cuatrecasas M, et al. Cancer 1997

35 These subtypes differ from each other with respect to: 1.Risk factors and precursor lesions 2.Patterns of spread 3.Molecular genetic alterations 4.Response to chemotherapy 5.Outcome

36 Ovarian Carcinomas: Stage at presentation (early vs advanced) according to Histologic Subtype Stage Clear Cell Endometrioid Mucinous Low-Grade Serous High-Grade Serous Carcinoma NOS I-II 26.2% 29.4% 8.5% 1.9% 30% 4.0% III-IV 4.9% 3.5% 1.1% 4.9% 84.2% 1.4% All 10.4% 10.3% 3.6% 3.5% 70% 2.1% Gilks CB et al. Mod Pathol 2009; 22:215A

37 Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis Retrograde menstruation Endometriosis Carcinoma Borderline tumor

38 Ovarian Atypical Endometriosis Endometrioid or Clear Cell Carcinomas 15-32% of cases

39 Genetic Alterations of Endometrioid Carcinomas of the Ovary Beta-Catenin 20-40% ARID1A 30% PTEN 15-20% PIK3CA 20% MSI 15% K-RAS 4-35% TP53 10%

40 Classification of Gyn Cancers based on Origin and Mutations Endometriosis Clear Cell Ca ARID 1A PIK3CA PTEN KRAS

41 Clear Cell Carcinoma Endometriotic Chocolate Cyst Adenofibroma

42 HNF-1B

43 Target Genes DPPIV Osteopontin ACE2 RBPMS FXYD2 TFPI2 LITAF/PIG7 ANXA4 UGT1A1 Ferritin ACE2 Free iron in the contents of endometrioma Antiapoptosis Ferritin Chronic oxidative stress Progesterone Detoxification Chemoresistance UGT1A1 ANXA4 Kobayashi H, et al. Int J Gynecol Cancer 2009 CPT-11 resistance Paclitaxel resistance hcg Osteopontin Rufix Glycogen Storage HNF-1beta DPPIV GLUT2 G6Pase G6P Glucokinase Glycogen synthase HNF-1 GLP-1 GIP Glucose HNF-3 Insulin Glucagon

44 Target Genes DPPIV Osteopontin ACE2 RBPMS FXYD2 TFPI2 LITAF/PIG7 ANXA4 UGT1A1 Ferritin ACE2 Free iron in the contents of endometrioma Antiapoptosis Ferritin Chronic oxidative stress Progesterone Detoxification Chemoresistance UGT1A1 ANXA4 Kobayashi H, et al. Int J Gynecol Cancer 2009 CPT-11 resistance Paclitaxel resistance hcg Osteopontin Rufix Glycogen Storage HNF-1beta DPPIV GLUT2 G6Pase G6P Glucokinase Glycogen synthase HNF-1 GLP-1 GIP Glucose HNF-3 Insulin Glucagon

45 Target Genes DPPIV Osteopontin ACE2 RBPMS FXYD2 TFPI2 LITAF/PIG7 ANXA4 UGT1A1 Ferritin ACE2 Free iron in the contents of endometrioma Antiapoptosis Ferritin Chronic oxidative stress Progesterone Detoxification Chemoresistance UGT1A1 ANXA4 Kobayashi H, et al. Int J Gynecol Cancer 2009 CPT-11 resistance Paclitaxel resistance hcg Osteopontin Rufix Glycogen Storage HNF-1beta DPPIV GLUT2 G6Pase G6P Glucokinase Glycogen synthase HNF-1 GLP-1 GIP Glucose HNF-3 Insulin Glucagon

46 Target Genes DPPIV Osteopontin ACE2 RBPMS FXYD2 TFPI2 LITAF/PIG7 ANXA4 UGT1A1 Ferritin ACE2 Free iron in the contents of endometrioma Antiapoptosis Ferritin Chronic oxidative stress Progesterone Detoxification Chemoresistance UGT1A1 ANXA4 Kobayashi H, et al. Int J Gynecol Cancer 2009 CPT-11 resistance Paclitaxel resistance hcg Osteopontin Rufix Glycogen Storage HNF-1beta DPPIV GLUT2 G6Pase G6P Glucokinase Glycogen synthase HNF-1 GLP-1 GIP Glucose HNF-3 Insulin Glucagon

47 Molecular Genetic Alterations in Clear Cell Carcinomas of Ovary ARID1A 46% PIK3CA 33% K-RAS 15-30% C-Met 22% Her-2 10% PPMD1D 10% PTEN 5% b-catenin 5% TP53 5%

48 Classification of Gyn Cancers based on Origin and Mutations Endometriosis? Fallopian Tube STIC Clear Cell Ca Endometrioid Ca High-grade Serous Ca ARID 1A PIK3CA PTEN KRAS CTNNB1 MSI PTEN ARID 1A TP53 BRCA1 Chromosomal instability Genetic chaos Endosalpingiosis

49 The five most common types of ovarian carcinoma High-grade serous Clear cell Endometrioid Mucinous Low-grade serous Usual stage at diagnosis Advanced Early Early Early Early or advanced Presumed tissue of origin /precursor lesion Fallopian tube or tubal metaplasia in inclusions of OSE Endometriosis, adenofibroma Endometriosis, adenofibroma Adenoma borderline carcinoma sequence; teratoma Serous borderline tumor Genetic risk BRCA1/2? HNPCC?? Significant molecular abnormalities p53 and prb pathway HNF-1β ARID1A PTEN, β- Catenin, K-ras MI, ARID1A K-ras BRAF or K-ras Proliferation High Low Low Intermediate Low Response to primary chemotherapy Prognosis 80% 15%? 15% 26-28% Poor Intermediate Favorable Favorable Favorable

50 Type I PIK3CA 20q amp KRAS BRAF ERB2 PTEN b-catenin Clear Cell Endometrioid Low-grade KRAS Mucinous TP53/Rb pathway Chromosomal instability Hig-grade Serous Type II

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52

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56 XIV CURSO DE PATOLOGIA ONCOLOGICA Barcelona, 4-6 de Noviembre de 2013 Servicio de Patología. Hospital de la Santa Creu i Sant Pau Universidad Autónoma de Barcelona Directores: Jaime Prat y Enrique Lerma TEMAS ESPECIALES Controversias Diagnósticas en Carcinomas de Tiroides John K C Chan Queen Elizabeth Hospital Hong Kong, China Patología Gastrointestinal Rhonda Yantiss New York Hospital-Weill Cornell Medical College Nueva York, EEUU Patología Ginecológica y Mamaria Quirúrgica Lugar de Celebración Hotel Alimara (****) Berruguete, Barcelona

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