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Clasificación del Cáncer de Ovario: Patología y Genética Molecular
Actualizaciones en Ginecologia y ObstetriciaXI Jornadas Nacionales - Gabinete Medico Velazquez
Madrid, 27 de febrero, 2014
Jaime PratHospital de la Santa Creu i Sant Pau
Universidad Autónoma de Barcelona
Surface epithelial ovarian tumors
Epithelial Ovarian Tumors ___________________________________________________________________________________________
Serous
Mucinous
Endometrioid
WHO 1999-2014
Endometrioid
Clear cell
Transitional
Squamous
Mixed
Undifferentiated
Benign60%
BL10%
Ca30%
EPITHELIAL OVARIAN TUMORSA heterogeneous group
____________________________________________
Histologic type, Precursor lesions, Genetic alterations …Histologic type, Precursor lesions, Genetic alterations …
Histologic Subtypes of Ovarian
Carcinomas
• Serous – high grade
• Serous – low grade• Serous – low grade
• Clear cell
• Endometrioid
• Mucinous
New classification: Frequency
HG serous
LG serous
Clear cellClear cell
Endometrioid
Mucinous
Unclassifiable
TP44
HGC
ECMC
LGSC
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 CarcinomaSerous Carcinoma
HEREDITARY SUSCEPTIBILITY
TO OVARIAN CANCER
BRCA2 (30%)BRCA2 (30%)
BRCA1 (65%)BRCA1 (65%)
Lifetime risk 30-60%
Lifetime risk 15-30%
HNPCC (7%) HNPCC (7%) Hereditary (10%)Hereditary (10%)
Sporadic (90%) Sporadic (90%)
Lifetime risk 30-60%
Rebbeck TR, Lynch HT, et al. NEJM 2002
Serous “Intraepithelial” Carcinoma
STIC
p53
Less than “STIC”?Less than “STIC”?
P53 Signature
BRCA Promotes P53 Signature to TIC
P53 signatureP53 signature TICTICNormalNormalP53P53
Hereditary : BRCA1 mutation constitutive
P53 signatureP53 signature TICTICNormalNormalP53P53
BRCA1
Hereditary : BRCA1 mutation constitutive
P53 signatureP53 signature TICTICNormalNormalP53P53 BRCA1BRCA1
Sporadic : BRCA1 methylation/mutation new event
P53 signatureP53 signature TICTICNormalNormalP53P53 BRCA1BRCA1
Sporadic :
Classification of Gyn Cancers based on Origin and Mutations
Fallopian Tube?
Endosalpingiosis
Fallopian Tube
STIC
TP53
BRCA1
Chromosomal
instability Genetic
chaos
High-grade Serous Ca
?
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.
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
Clinical Staging of Ovarian Cancer (FIGO 1988)
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.
Clinical Staging of Cancer of the Ovary
Fallopian Tube and Peritoneum
(FIGO 2012)
FIGO Committee for Gynaecologic Oncology
Rome, October 7th, 2012
(FIGO 2012)
OV Primary tumor, ovary FT Primary tumor, fallopian tubeP Primary tumor, peritoneumX 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 washingsNo 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 T2atubes/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 exclusivelyRetroperitoneal 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)
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)
IIIA2 Microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph nodes
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, M1Any T, Any N, M1
HGSC – Pathogenetic Model
DDL Bowtell Nature Rev Cancer 2010
Chromosomes from six ovarian cancers showing:
chromosomal instability
1 2 3
4 5
6 7 8
9 10 11
12 13 14 15 16
17 18
19 20
21 22 X
1 2 3
4 5
6 7 8 9
10 11
12 13 14 15
16 17 18
19 20
21 22 X
A B
C D
1 2 3
4 5
6 7 8 9
10 11
12 13 14 15
16 17 18
19 20
21 22 X
1 2
3 4 5
6 7 8
9 10 11
12 13 14 15
16 17 18
19 20
21 22 X
1 2 3
4 5
6 7 8 9
10 11 12
13 14 15
16 17 18
19 20 21 22
X
1 2 3
4 5
6 7 8 9
10 11
12 13 14 15
16 17 18
19 20
21 22 X
C D
E F
Serous carcinoma, G3
Low grade High grade
MPSCa
SBT + MPSCa
Serous Borderline Tumor
Noninvasive epithelial implant
• Non-invasive
- Epithelial
- Desmoplastic
• InvasiveBell DA, et al
Cancer 1988; 62:2212
Peritoneal Implants
(SBT)
Noninvasive epithelial implant
Noninvasive (desmoplastic) implant Invasive implant
Serous Tumors(Pathogenesis - Dualistic model)
KRAS and BRAF mutations (70%)
Low Gr Serous CaMP Ca (Inv)SBT-MPSBTBg
High Grade Serous Ca
KRAS and BRAF mutations (70%)
Singer et alAm J Pathol 2002
p53 mutations, LOH 17q (80%)
HER-2/neu amplification/overexpression
BRCA inactivation (80%)
Mucinous Tumors of the Ovary(From benign to malignant)
1960s
Adenoma Carcinoma
Ca
1970s Borderline
Ca
1980s Metastatic Ca
Ca
1990s Appendiceal t + PP
Ca
Mucinous Tumors(Ovary)
• Benign 75% 80%• Benign 75%
• Borderline 10%
• Carcinomas 15%
Koonings, 1998
80%
17%
3%
Mucinous glands
CystadenomaCarcinoma Cystadenoma
Borderline
Carcinoma
Epithelial Ovarian TumorsK-ras Mutations (12, 13)
56
73 25
20Benign
Borderline
0 20 40 60 80 10020406080100
3585
73 25Borderline
Malignant
(%) Mucinous (%) Non-MucinousCuatrecasas M, et al. Cancer 1997
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
Stage Clear
Cell
Endometrioid Mucinous Low-Grade
Serous
Carcinoma
NOS
High-Grade
Serous
Ovarian Carcinomas:Stage at presentation (early vs advanced) according to
Histologic Subtype
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
Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis
Retrograde menstruation
Carcinoma
Endometriosis
Borderline
tumor
Carcinoma
Ovarian Atypical Endometriosis →Endometrioid or Clear Cell Carcinomas
15-32% of cases
Beta-Catenin 20-40%
ARID1A 30%
Genetic Alterations of Endometrioid
Carcinomas of the Ovary
ARID1A 30%
PTEN 15-20%
PIK3CA 20%
MSI 15%
K-RAS 4-35%
TP53 10%
Clear Cell Carcinoma
AdenofibromaEndometriotic Chocolate Cyst
ARID1A 46%
PIK3CA 33%
K-RAS 15-30%
C-Met 22%
Molecular Genetic Alterations in Clear CellCarcinomas of Ovary
C-Met 22%
Her-2 10%
PPMD1D 10%
PTEN 5%
b-Catenin 5%
TP53 5%
Classification of Gyn Cancers based on Origin and Mutations
Fallopian Tube?
Endometriosis
Endosalpingiosis
Fallopian Tube
STIC
TP53
BRCA1
Chromosomal
instability Genetic
chaos
High-grade Serous Ca
?
Endometrioid Ca
CTNNB1
MSI
PTEN
ARID 1A
Clear Cell Ca
ARID 1A
PIK3CA
PTEN
KRAS
High-grade serous
Clear cell Endometrioid Mucinous Low-grade serous
Usual stage at diagnosis
Presumed tissue oforigin /precursor lesion
Advanced Early Early EarlyEarly or
advanced
Fallopian tube or
tubal metaplasia
in inclusions of
OSE
Endometriosis,
adenofibroma
Endometriosis,
adenofibroma
Adenoma–
borderline –
carcinoma
sequence;
teratoma
Serous
borderline
tumor
The five most common types of ovarian carcinoma
Response to primary chemotherapy
Genetic risk
Significant molecular abnormalities
Proliferation
Prognosis Poor Intermediate Favorable Favorable Favorable
80% 15% ? 15% 26-28%
High Low Low Intermediate Low
p53 and pRb
pathway HNF-1β
ARID1A
PTEN, β-
Catenin, K-ras
MI, ARID1A
K-rasBRAF or
K-ras
BRCA1/2 ? HNPCC ? ?
Mucinous
Clear Cell
PIK3CA20q amp
PTENb-catenin
KRAS TP53/Rb pathwayChromosomal
instability
Hig-grade SerousClear Cell
KRASBRAFERB2
Hospital de la Santa Creu i Sant Pau