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