Clasificación histopatológica del cáncer de ovario
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Clasificación histopatológica del cáncer de ovario

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Ponente: Jaime de Prat Díaz de Losada. Hospital de la Santa Creu i Sant Pau. Barcelona

Ponente: Jaime de Prat Díaz de Losada. Hospital de la Santa Creu i Sant Pau. Barcelona

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Clasificación histopatológica del cáncer de ovario Clasificación histopatológica del cáncer de ovario Presentation Transcript

  • Actualizaciones en Ginecologia y Obstetricia XI Jornadas Nacionales - Gabinete Medico Velazquez Madrid, 27 de febrero, 2014 Clasificación del Cáncer de Ovario: Patología y Genética Molecular Jaime Prat Hospital de la Santa Creu i Sant Pau Universidad Autónoma de Barcelona
  • Surface epithelial ovarian tumors
  • Epithelial Ovarian Tumors ___________________________________________________________________________________________ WHO 1999-2014 Serous Mucinous Endometrioid Clear cell Transitional Squamous Mixed Undifferentiated Benign 60% BL 10% Ca 30%
  • EPITHELIAL OVARIAN TUMORS A heterogeneous group ____________________________________________ Histologic type, Precursor lesions, Genetic alterations …
  • Histologic Subtypes of Ovarian Carcinomas • • • • • Serous – high grade Serous – low grade Clear cell Endometrioid Mucinous
  • New classification: Frequency HG serous LG serous Clear cell Endometrioid Mucinous Unclassifiable TP44
  • HGC LGSC MC EC CCC
  • 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
  • Biomarker profiles across subtypes Köbel M et al. PLoS Med 2008; 5:e232
  • Serous Carcinoma
  • HEREDITARY SUSCEPTIBILITY TO OVARIAN CANCER BRCA2 (30%) Lifetime risk 15-30% BRCA1 (65%) Lifetime risk 30-60% HNPCC (7%) Hereditary (10%) Rebbeck TR, Lynch HT, et al. NEJM 2002 Sporadic (90%)
  • Serous “Intraepithelial” Carcinoma STIC p53
  • Less than “STIC”?
  • P53 Signature
  • BRCA Promotes P53 Signature to TIC Normal Hereditary : Normal BRCA1 P53 BRCA1 mutation constitutive P53 Sporadic : TIC TIC P53 signature P53 signature BRCA1 BRCA1 methylation/mutation new event TIC
  • Classification of Gyn Cancers based on Origin and Mutations ? Fallopian Tube STIC High-grade Serous Ca TP53 BRCA1 Chromosomal instability Genetic chaos Endosalpingiosis
  • STIC P53 High Grade Serous Carcinoma
  • SBT in epithelial inclusion cyst
  • Inconsistent association between STIC and High-Grade Serous Carcinoma (HGSC) • Asymptomatic BRCA+ women - increased risk of HGSC and 6% have STIC at risk-reduction salpingo-oophorectomy (RRSO) • Symptomatic BRCA+ tumors discovered at advanced stage (in younger patients) are less likely to be associated with STIC and are rapidly progressive. • Effectiveness of salpingectomy alone in preventing HGSC in BRCA+ women? • Tube linked to only some HGSCs. Nearby peritoneum/ovarian surface epithelium also hosts progenitors to this malignancy.
  • Clinical Staging of Ovarian Cancer (FIGO 1988) I Limited to ovaries Ia One ovary; capsule intact; no tumor on surface; washings and ascites free of malignant cells Ib Both ovaries; capsule intact; no tumor on surface; washings and ascites free of malignant cells Ic Any of above, but with tumor on surface, or capsule ruptured (spontaneous or iatrogenic), or positive ascites or positive peritoneal washings II One or both ovaries with pelvic extension IIa Extension and/or metastases to uterus and/or tubes IIb Extension to other pelvic tissues IIc Any of above, but with tumor on surface, or capsule ruptured, or ascites or positive peritoneal washings III One or both ovaries with microscopically confirmed peritoneal metastases outside the pelvis and/or positive regional lymph nodes. IIIa Microscopic peritoneal metastases beyond pelvis IIIb Macroscopic peritoneal metastases beyond pelvis ≤ 2 cm IIIc Peritoneal metastases beyond pelvis >2 cm or positive regional lymph nodes IV Distant metastases beyond peritoneal cavity. Liver metastases must be parenchymal (liver capsule metastases is stage III). If pleural effusion present, positive cytology required.
  • FIGO Committee for Gynaecologic Oncology Rome, October 7th, 2012 Clinical Staging of Cancer of the Ovary Fallopian Tube and Peritoneum (FIGO 2012) OV FT P X Primary tumor, ovary Primary tumor, fallopian tube Primary tumor, peritoneum Primary tumor cannot be assessed
  • I Tumor confined to ovaries or fallopian tube(s) T1 IA Tumor limited to one ovary (capsule intact) or fallopian tube, T1a No tumor on ovarian or fallopian tube surface No malignant cells in the ascites or peritoneal washings IB Tumor limited to both ovaries (capsules intact) or fallopian tubes T1b No tumor on ovarian or fallopian tube surface No malignant cells in the ascites or peritoneal washings IC Tumor limited to one or both ovaries or fallopian tubes, T1c with any of the following: IC1 Surgical spill IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface IC3 Malignant cells in the ascites or peritoneal washings
  • II Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancer T2 IIA Extension and/or implants on the uterus and/or fallopian tubes/and/or ovaries T2a IIB Extension to other pelvic intraperitoneal tissues T2b IIC Any of above, but with ascites or positive peritoneal washings
  • Ovarian Carcinomas involving Retroperitoneal LNs • Less than 10% of ovarian carcinomas have extended beyond the pelvis with exclusively Retroperitoneal Lymph Node involvement • Literature evidence indicates that these cases have better prognosis than tumors with abdominal peritoneal involvement • No pathological distinction between high-grade serous and low-grade serous carcinomas
  • New Stage III - FIGO 2012 III One or both ovaries, fallopian tubes, or primary peritoneal cancer with pathologically proved spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes IIIA Metastasis to the retroperitoneal lymph nodes with or without microscopic peritoneal involvement beyond the pelvis IIIA1 Positive retroperitoneal lymph nodes only IIIA1(i) Metastasis (≤ 1 cm in size) IIIA1(ii) Metastasis (> 1 cm in size) IIIA2 Microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph nodes IIIB Macroscopic peritoneal metastasis beyond the pelvis 2 cm or less with or without metastasis to the retroperitoneal lymph nodes IIIC Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm with or without metastasis to the retroperitoneal lymph nodes (Note 1: includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)
  • Stage IV • Stage IVA: Pleural effusion with positive cytology • Stage IVB: Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of abdominal cavity) Any T, Any N, M1
  • HGSC – Pathogenetic Model DDL Bowtell Nature Rev Cancer 2010
  • Chromosomes from six ovarian cancers showing: chromosomal instability B A 1 1 2 4 2 3 4 3 5 5 6 6 9 7 11 10 7 10 8 8 12 12 13 18 17 C 19 21 14 20 22 15 16 16 13 18 17 19 21 X 2 4 X D 2 4 3 3 5 6 7 10 8 7 10 9 8 11 9 12 11 12 13 16 17 19 21 14 13 16 15 14 19 X X 18 20 1 2 4 2 4 5 10 7 11 8 13 16 17 19 14 15 8 13 17 14 18 18 19 X 21 9 11 16 20 22 3 7 10 12 12 22 5 6 9 21 F 1 6 15 17 18 20 22 3 21 15 5 6 E 14 20 22 1 1 9 11 20 22 X 15
  • Serous carcinoma, G3
  • Low grade High grade
  • SBT + MPSCa MPSCa
  • Serous Borderline Tumor
  • Peritoneal Implants (SBT) • Non-invasive - Epithelial - Desmoplastic • Invasive Bell DA, et al Cancer 1988; 62:2212 Noninvasive (desmoplastic) implant Noninvasive epithelial implant Invasive implant
  • 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
  • Mucinous Tumors of the Ovary (From benign to malignant) Adenoma Carcinoma 1960s Ca 1970s Borderline Ca 1980s Metastatic Ca Ca 1990s Appendiceal t + PP
  • Mucinous Tumors (Ovary) • Benign • Borderline • Carcinomas 75% 10% 15% Koonings, 1998 80% 17% 3%
  • Mucinous glands Cystadenoma Carcinoma Borderline
  • Epithelial Ovarian Tumors K-ras Mutations (12, 13) Benign 56 Borderline Malignant 20 73 25 85 100 35 80 60 40 (%) Mucinous 20 0 20 40 60 80 (%) Non-Mucinous Cuatrecasas M, et al. Cancer 1997 100
  • 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
  • Ovarian Carcinomas: Stage at presentation (early vs advanced) according to Histologic Subtype Stage Clear Cell I-II 26.2% III-IV All Endometrioid Mucinous Low-Grade Serous High-Grade Serous Carcinoma NOS 29.4% 8.5% 1.9% 30% 4.0% 4.9% 3.5% 1.1% 4.9% 84.2% 1.4% 10.4% 10.3% 3.6% 3.5% 70% 2.1% Gilks CB et al. Mod Pathol 2009; 22:215A
  • Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis Retrograde menstruation Carcinoma Endometriosis Borderline tumor
  • Ovarian Atypical Endometriosis → Endometrioid or Clear Cell Carcinomas 15-32% of cases
  • Genetic Alterations of Endometrioid Carcinomas of the Ovary Beta-Catenin ARID1A PTEN PIK3CA MSI K-RAS TP53 20-40% 30% 15-20% 20% 15% 4-35% 10%
  • Clear Cell Carcinoma Endometriotic Chocolate Cyst Adenofibroma
  • Molecular Genetic Alterations in Clear Cell Carcinomas of Ovary ARID1A PIK3CA K-RAS C-Met Her-2 PPMD1D PTEN b-Catenin TP53 46% 33% 15-30% 22% 10% 10% 5% 5% 5%
  • Classification of Gyn Cancers based on Origin and Mutations Endometriosis ? Fallopian Tube STIC Clear Cell Ca ARID 1A PIK3CA PTEN KRAS Endometrioid Ca CTNNB1 MSI PTEN ARID 1A High-grade Serous Ca TP53 BRCA1 Chromosomal instability Genetic chaos Endosalpingiosis
  • The five most common types of ovarian carcinoma Low-grade serous High-grade serous Usual stage at diagnosis Presumed tissue of origin /precursor lesion Clear cell Endometrioid Mucinous Advanced Early Early Early Early or advanced Endometriosis, adenofibroma Adenoma– borderline – carcinoma sequence; teratoma Serous borderline tumor ? HNPCC ? ? HNF-1β ARID1A PTEN, βCatenin, K-ras MI, ARID1A K-ras BRAF or K-ras Fallopian tube or tubal metaplasia Endometriosis, in inclusions of adenofibroma OSE Genetic risk BRCA1/2 Significant molecular abnormalities p53 and pRb pathway Proliferation High Low Low Intermediate Low Response to primary chemotherapy 80% 15% ? 15% 26-28% Prognosis Poor Intermediate Favorable Favorable Favorable
  • PTEN b-catenin KRAS Mucinous TP53/Rb pathway Chromosomal instability PIK3CA 20q amp Clear Cell KRAS BRAF ERB2 Hig-grade Serous
  • Hospital de la Santa Creu i Sant Pau