Epithelial Ovarian Cancer - University of Kentucky

Epithelial Ovarian Cancer


Fred Ueland, MD

University of Kentucky

Gynecologic Oncology

Fred Ueland, MD

Fred Ueland, MD





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


Ovarian Cancer

Ovarian Cancer

Ovarian Cancer



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










Serous Ovarian Cancer




Endometrioid Ovarian Cancer




Undifferentiated Ovarian Cancer

Undifferentiated Ovarian Cancer

Metastasis

Metastasis

Familial Ovarian Cancer


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


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


•

•

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



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

–

–

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


36

36

-

-

85% get breast cancer

85% get breast cancer

–

–



p53

p53

Regulates cell cycle

Regulates cell cycle

–

–

“Guardian of the genome”

“Guardian of the genome”

–

–

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.



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





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


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



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

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Epithelial Ovarian Cancer - University of Kentucky