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

1. 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

2. Surface epithelial ovarian tumors

3. Epithelial Ovarian Tumors
___________________________________________________________________________________________
WHO 1999-2014
Serous
Mucinous
Endometrioid
Clear cell
Transitional
Squamous
Mixed
Undifferentiated
Benign
60%
BL
10%
Ca
30%

4. EPITHELIAL OVARIAN TUMORS
A heterogeneous group
____________________________________________
Histologic type, Precursor lesions, Genetic alterations …

5. Histologic Subtypes of Ovarian
Carcinomas
•
•
•
•
•
Serous – high grade
Serous – low grade
Clear cell
Endometrioid
Mucinous

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

7. HGC
LGSC
MC
EC
CCC

8. 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

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

10. Serous Carcinoma

11. 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%)

12. Serous “Intraepithelial” Carcinoma
STIC
p53

13. Less than “STIC”?

14. P53 Signature

16. 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

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

18. STIC
P53
High Grade Serous Carcinoma

19. SBT in epithelial inclusion cyst

20. 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.

21. 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.

23. 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

24. 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

25. 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

26. 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

27. 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)

28. 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

29. HGSC – Pathogenetic Model
DDL Bowtell Nature Rev Cancer 2010

30. 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

31. Serous carcinoma, G3

32. Low grade
High grade

33. SBT + MPSCa
MPSCa

34. Serous Borderline Tumor

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

36. 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

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

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

39. Mucinous
glands
Cystadenoma
Carcinoma
Borderline

41. 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

42. 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

43. 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

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

45. Ovarian Atypical Endometriosis →
Endometrioid or Clear Cell Carcinomas
15-32% of cases

46. 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%

47. Clear Cell Carcinoma
Endometriotic Chocolate Cyst
Adenofibroma

48. 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%

49. 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

50. 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

51. PTEN
b-catenin
KRAS
Mucinous
TP53/Rb pathway
Chromosomal
instability
PIK3CA
20q amp
Clear Cell
KRAS
BRAF
ERB2
Hig-grade Serous

52. Hospital de la Santa Creu i Sant Pau