Epithelial Ovarian Cancer - University of Kentucky
Transcript of Epithelial Ovarian Cancer - University of Kentucky
Epithelial Ovarian Cancer
Epithelial Ovarian Cancer
Fred Ueland, MD
University of Kentucky
Gynecologic Oncology
Fred Ueland, MD
Fred Ueland, MD
University of Kentucky
University of Kentucky
Gynecologic Oncology
Gynecologic Oncology
Risk Factors
Risk Factors
Incessant ovulation
Incessant ovulation
–
–
Early menarche, late menopause, low parity
Early menarche, late menopause, low parity
Family history
Family history
–
–
Acquired genetic mutations
Acquired genetic mutations
–
–
BRCA
BRCA
-
-
1,2 and HNPCC
1,2 and HNPCC
Fertility drugs
Fertility drugs
–
–
Clomid
Clomid
,
,
Pergonal
Pergonal
High fat diet
High fat diet
–
–
Western hemisphere
Western hemisphere
Talc
Talc
Incidence and Mortality
Incidence and Mortality
Ovarian Cancer
Ovarian Cancer
Ovarian Cancer
Incidence and Mortality
Incidence and Mortality
Data from the
Data from the
American Cancer
American Cancer
Society
Society
200 deaths in Kentucky in 2006
200 deaths in Kentucky in 2006
Incidence
Incidence
Mortality
Mortality
Classification
Classification
Ovarian Cancer
Histology
Histology
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Low Malignant Potential
Serous Ovarian Cancer
Serous Ovarian Cancer
Serous Ovarian Cancer
Serous Ovarian Cancer
Endometrioid Ovarian Cancer
Endometrioid Ovarian Cancer
Endometrioid Ovarian Cancer
Endometrioid Ovarian Cancer
Undifferentiated Ovarian Cancer
Undifferentiated Ovarian Cancer
Metastasis
Metastasis
Familial Ovarian Cancer
Familial Ovarian Cancer
Ovarian Cancer
Familial Ovarian Cancer
Familial Ovarian Cancer
Site
Site
-
-
specific ovarian cancer
specific ovarian cancer
–
–
2 or more 1
2 or more 1
st
st
degree relatives
degree relatives
–
–
Ovarian cancer only
Ovarian cancer only
Breast
Breast
-
-
ovarian cancer syndrome
ovarian cancer syndrome
–
–
BRCA 1,2
BRCA 1,2
–
–
Over 50% develop cancer by age 70
Over 50% develop cancer by age 70
Lynch II syndrome
Lynch II syndrome
–
–
HNPCC
HNPCC
Genetic Mutations
Genetic Mutations
Ovarian Cancer
Ovarian Cancer
Tumor Suppressor Genes
Tumor Suppressor Genes
P53 most frequent (60
P53 most frequent (60
-
-
70%), poor
70%), poor
px
px
P16 in 15%
P16 in 15%
BRCA
BRCA
-
-
1 17q (5%), BRCA
1 17q (5%), BRCA
-
-
2 13q (3%)
2 13q (3%)
•
•
Autosomal dominant, 80% penetrance
Autosomal dominant, 80% penetrance
•
•
90% are frame shift, 10% missense
90% are frame shift, 10% missense
•
•
Ashkenazi Jews 5
Ashkenazi Jews 5
-
-
10 x
10 x
↑
↑
risk of mutations
risk of mutations
PTEN in endometrioid cell type
PTEN in endometrioid cell type
Tumor Suppressor Genes
Tumor Suppressor Genes
1.
1.
Discovered in 1980’s
Discovered in 1980’s
2.
2.
Inhibitory
Inhibitory
3.
3.
Heritable, early in genesis
Heritable, early in genesis
Knudson’s two
Knudson’s two
-
-
hit hypothesis
hit hypothesis
4.
4.
Loss of heterozygosity (LOH)
Loss of heterozygosity (LOH)
5.
5.
Gate keepers inhibit cell proliferation,
Gate keepers inhibit cell proliferation,
promote apoptosis
promote apoptosis
RB (13q), p53 (17p), APC (5q21)
RB (13q), p53 (17p), APC (5q21)
BRCA1 (17q), BRCA2 (13q)
BRCA1 (17q), BRCA2 (13q)
BRCA
BRCA
-
-
1,2
1,2
Tumor suppressor gene common to all
Tumor suppressor gene common to all
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–
DNA repair gene
DNA repair gene
–
–
Over 600 mutations known
Over 600 mutations known
BRCA 1 (17q21), BRCA 2 (13q12)
BRCA 1 (17q21), BRCA 2 (13q12)
Ashkenazi Jew 2.3%
Ashkenazi Jew 2.3%
–
–
5 fold
5 fold
+
+
increase
increase
16
16
-
-
60% get ovarian cancer
60% get ovarian cancer
–
–
8 to 30 fold increase
8 to 30 fold increase
36
36
-
-
85% get breast cancer
85% get breast cancer
–
–
3 to 7 fold increase
3 to 7 fold increase
p53
p53
Regulates cell cycle
Regulates cell cycle
–
–
“Guardian of the genome”
“Guardian of the genome”
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–
17p13
17p13
p53 “wild type” is the functional gene
p53 “wild type” is the functional gene
Activated with DNA damage
Activated with DNA damage
–
–
blocks replication and allows for repair
blocks replication and allows for repair
For irreversible DNA damage, p53 initiates
For irreversible DNA damage, p53 initiates
apoptosis
apoptosis
Mutated p53 can not initiate cellular arrest or
Mutated p53 can not initiate cellular arrest or
apoptosis
apoptosis
–
–
Cell replicates the aberrant DNA
Cell replicates the aberrant DNA
p53
p53
Present in 50% of all cancers
Present in 50% of all cancers
Li
Li
-
-
Fraumeni
Fraumeni
–
–
50 different mutations
50 different mutations
–
–
Risk for
Risk for
osteo
osteo
and soft tissues sarcomas,
and soft tissues sarcomas,
breast, brain, adrenal cancers, leukemias…
breast, brain, adrenal cancers, leukemias…
Bladder cancer
Bladder cancer
–
–
20
20
-
-
40%
40%
Breast cancer
Breast cancer
–
–
20
20
-
-
40%
40%
Genetic Mutations
Genetic Mutations
Ovarian Cancer
Ovarian Cancer
Oncogenes
Oncogenes
Her
Her
-
-
2/neu (20
2/neu (20
-
-
30%), poor
30%), poor
px
px
C
C
-
-
myc
myc
(20
(20
-
-
30%)
30%)
K
K
-
-
ras (5%)
ras (5%)
•
•
50% of mucinous tumors
50% of mucinous tumors
•
•
LMP (20
LMP (20
-
-
50%)
50%)
Genetic Mutations
Genetic Mutations
Ovarian Cancer
Ovarian Cancer
DNA Repair Genes
DNA Repair Genes
Mismatch repair genes
Mismatch repair genes
•
•
MSH
MSH
2
2
, MLH
, MLH
1
1
, MSH
, MSH
6
6
, PMS
, PMS
1
1
, PMS
, PMS
2
2
HNPCC syndrome
HNPCC syndrome
•
•
5
5
-
-
10% will develop OC
10% will develop OC
•
•
Breast cancer not linked
Breast cancer not linked
DNA Repair Genes
DNA Repair Genes
I.
I.
Autosomal dominant, 80% penetrance
Autosomal dominant, 80% penetrance
II.
II.
Maintain genomic integrity by repairing mismatched
Maintain genomic integrity by repairing mismatched
DNA before replication
DNA before replication
III.
III.
MSH
MSH
2
2
, MLH
, MLH
1
1
, MSH
, MSH
6
6
, PMS
, PMS
1
1
, PMS
, PMS
2
2
IV.
IV.
HNPCC syndrome (Lynch II)
HNPCC syndrome (Lynch II)
Proximal colorectal
Proximal colorectal
80% lifetime risk
80% lifetime risk
Endometrial
Endometrial
40%
40%
Gastric
Gastric
20%
20%
Ovarian
Ovarian
9%
9%
Hepatobiliary
Hepatobiliary
Urinary
Urinary
Staging
Staging
Ovarian Cancer
Ovarian Cancer
Stage Distribution and
Stage Distribution and
Outcome
Outcome
50%
50%
Overall
Overall
0
0
-
-
20%
20%
15
15
IV
IV
15
15
-
-
30%
30%
55
55
III
III
65%
65%
6
6
II
II
95%
95%
24
24
I
I
Survival
Survival
Percent
Percent
Stage
Stage
American
American Cancer Society
Stage I
Stage I
Confined to ovaries
Confined to ovaries
Stage IA: Confined to one ovary
Stage IA: Confined to one ovary
Stage IB: Both ovaries
Stage IB: Both ovaries
Stage IC: One or both ovaries and:
Stage IC: One or both ovaries and:
–
–
Surface involvement
Surface involvement
–
–
Capsule ruptured
Capsule ruptured
–
–
(+) washings from the abdomen/pelvis
(+) washings from the abdomen/pelvis
Stage II
Stage II
Confined to Pelvis
Confined to Pelvis
Stage IIA: Involvement of uterus or the
Stage IIA: Involvement of uterus or the
fallopian tubes, or both.
fallopian tubes, or both.
Stage IIB: Adjacent pelvic organs
Stage IIB: Adjacent pelvic organs
–
–
bladder, sigmoid colon, or the rectum.
bladder, sigmoid colon, or the rectum.
Stage IIC: IIA or IIB with (+) washings
Stage IIC: IIA or IIB with (+) washings
Stage III
Stage III
Extrapelvic Disease
Extrapelvic Disease
Stage IIIA: Microscopic disease of upper
Stage IIIA: Microscopic disease of upper
abdomen
abdomen
Stage IIIB: Upper abdominal involvement,
Stage IIIB: Upper abdominal involvement,
but less than 2 cm in size
but less than 2 cm in size
Stage IIIC:
Stage IIIC:
–
–
Lymph node involvement.
Lymph node involvement.
–
–
Upper abdominal disease
Upper abdominal disease
≥
≥
2 cm
2 cm
Stage IV
Stage IV
Distant Spread
Distant Spread
Stage IV: Distant metastasis
Stage IV: Distant metastasis
–
–
Liver parenchyma
Liver parenchyma
–
–
Lungs
Lungs
–
–
Pleural fluid
Pleural fluid
–
–
Other distant organs located outside of the
Other distant organs located outside of the
peritoneal cavity
peritoneal cavity
Surgery
Surgery
Ovarian Cancer
Ovarian Cancer
Ovarian Cancer
Ovarian Cancer
Ovarian Cancer
Ovarian Cancer
Epithelial Ovarian Cancer
Epithelial Ovarian Cancer
Epithelial Ovarian Cancer
Epithelial Ovarian Cancer
Role Surgery
Role Surgery
Proper staging for early disease
Proper staging for early disease
–
–
Adjuvant therapy
Adjuvant therapy
Cytoreduction of advanced disease
Cytoreduction of advanced disease
–
–
Optimal
Optimal
≤
≤
1cm
1cm
Reassessment laparotomy
Reassessment laparotomy
Secondary debulking
Secondary debulking
GOG Surgical Procedures
GOG Surgical Procedures
Manual
Manual
Adequate abdominal incision
Adequate abdominal incision
Estimate volume of peritoneal fluid. If no
Estimate volume of peritoneal fluid. If no
fluid, obtain washings from pelvis and
fluid, obtain washings from pelvis and
abdomen if suspected stage I or II
abdomen if suspected stage I or II
Inspect all peritoneal surfaces
Inspect all peritoneal surfaces
Infra
Infra
-
-
colic omentectomy
colic omentectomy
–
–
At minimum, a biopsy must be obtained
At minimum, a biopsy must be obtained
GOG Surgical Procedures
GOG Surgical Procedures
Manual
Manual
If possible, extrafascial TAH with BSO. Unilateral SO if
If possible, extrafascial TAH with BSO. Unilateral SO if
patient desires fertility and cancer appears stage I
patient desires fertility and cancer appears stage I
Resect all remaining gross disease in abdomen pelvis
Resect all remaining gross disease in abdomen pelvis
Selective pelvic and para
Selective pelvic and para
-
-
aortic lymph node sampling
aortic lymph node sampling
–
–
Not required if stage
Not required if stage
IIIc
IIIc
or IV, except for cytoreduction
or IV, except for cytoreduction
If no gross disease, perform peritoneal biopsies
If no gross disease, perform peritoneal biopsies
–
–
Cul
Cul
-
-
de
de
-
-
sac
sac
–
–
Vesical peritoneum
Vesical peritoneum
–
–
Right and left pelvic sidewalls
Right and left pelvic sidewalls
–
–
Right and left paracolic gutters
Right and left paracolic gutters
–
–
Right hemidiaphragm
Right hemidiaphragm
Cytoreduction
Cytoreduction
Ovarian Cancer
Ovarian Cancer
Slide courtesy of Gynecologic Cancer Foundation
Value of Specialists
Value of Specialists
Meta
Meta
-
-
analysis (18 studies) concluded marked benefit with
analysis (18 studies) concluded marked benefit with
Gynecologic Oncologist (Giede 2005)
Gynecologic Oncologist (Giede 2005)
–
–
Complete surgical staging with early stage disease
Complete surgical staging with early stage disease
–
–
Optimal cytoreductive surgery with advanced disease
Optimal cytoreductive surgery with advanced disease
–
–
Improved median and overall survival
Improved median and overall survival
Others supporting GO involvement:
Others supporting GO involvement:
–
–
NCCN guidelines
NCCN guidelines
–
–
SGO, ACOG
SGO, ACOG
–
–
SOGC clinical practice guidelines
SOGC clinical practice guidelines
–
–
NIH consensus statement
NIH consensus statement
–
–
London Medical Advisory statement
London Medical Advisory statement
17.5%
17.5%
IV
IV
31.5%
31.5%
IIIC
IIIC
42.4%
42.4%
IIIB
IIIB
50.8%
50.8%
IIIA
IIIA
64.4%
64.4%
IIC
IIC
72.4%
72.4%
IIB
IIB
78.6%
78.6%
IIA
IIA
84.7%
84.7%
IC
IC
85.4%
85.4%
IB
IB
92.7%
92.7%
IA
IA
Overall Survival
Overall Survival
Improving Survival
Improving Survival
Conclusions
Conclusions
1.
1.
Advanced stage presentation
Advanced stage presentation
•
•
50% overall five
50% overall five
-
-
year survival
year survival
2.
2.
Serous histology most common
Serous histology most common
3.
3.
Familial ovarian cancer
Familial ovarian cancer
•
•
site
site
-
-
specific
specific
•
•
breast ovarian
breast ovarian
•
•
Lynch II syndrome
Lynch II syndrome
Conclusions
Conclusions
1.
1.
Always prepared for surgical
Always prepared for surgical
staging
staging
2.
2.
Optimal surgical debulking
Optimal surgical debulking
improves overall patient survival
improves overall patient survival
3.
3.
Early involvement of gynecologic
Early involvement of gynecologic
oncologist improves overall
oncologist improves overall
patient survival
patient survival