Endometriosis associated ovarian cancer - PowerPoint Presentation

Slide1

Endometriosis associated ovarian cancer

SH-Sheikh

hasani

GYN.Oncologist

Imamkhomeini

Hospital

Slide2

Prevalence of Ovarian Cancer

the most lethal

gynaecological

tumor

prevalence

:

3.7

%

of all female cancers and for 4.2% of

all oncologic

deaths in women every year

Slide3

>

90% of ovarian tumors have epithelial origin,

rest of

them

arise

from

germcells

or

granulosa

-theca

cells

.

Of all epithelial tumors, about

60–70%

serous,

5% mucinous

, and

15%

either

endometrioid

and clear-cell.

serous ovarian carcinomas can

be further

subdivided

in high-

(90–95%) and low-grade (5–10%)

Slide4

ovarian cancer has been

divided into

two

subgroups: type I and type II

Type I

:

low-grade and

borderline serous,

endometrioid

, mucinous, and clear-cell carcinomas

.

The most frequent mutations in this

type:

KRAS, BRAF, ERBB2, PTEN,

PIK3CA,b-catenin

gene (CTNNB1), and ARID1A and

PPP2R1A

Slide5

TypeII:

high-grade serous,

mixedmalignant

mesodermal,

carcinosarcomas

, and

undifferenti-ated

tumors

include the majority of epithelial tumors,

more

aggressive

,

in up to 95% of patients

TP53

is

affected by a mutation

Slide6

Pathogenesis of Epithelial Ovarian Cancer

Slide7

Slide8

Endometriosis-AssociatedOvarianCancer (EAOC).

The relationship

between endometriosis and ovarian cancer

was firstly

described by Sampson in

1927.

following criteria for diagnosing the carcinomatous

development

in endometriosis:

(

1) coexistence of carcinoma

and endometriosis

within the same ovary

,

(2) a similar

histological pattern

(3) exclusion of a second malignant

tumor elsewhere.

In 1953, Scott has added a fourth

criterion:

demonstration of a histology-proven transition

from benign

endometriosis to cancer

Slide9

prevalence of ovarian cancer

ranging

0.7

% to 17%

of

women with

endometriosis

The

Association between

Endometriomas

and Ovarian

Cancer: Preventive Effect of Inhibiting Ovulation

and Menstruation

during Reproductive

Life Giovanni

Grandi,Angela

Toss

,

Slide10

Up to dateThe risk of malignant transformation of

endometriosis estimated :

1 percent for premenopausal

women

1

to 2.5 percent for postmenopausal

women.

In a study of women with postmenopausal endometriosis, 35 percent (20 of 57) had different grades of metaplasia, hyperplasia,

atypia

, and

endometrioid

carcinoma arising in ovarian

endometriosis.

Slide11

Slide12

Slide13

Histologically benign endometriosis may harbor genetic abnormalities

that predispose for malignant

transformation

.

Mutations

of ARID1A

have been demonstrated in

atypical endometriosis

,

ARID1A mutations are

an

early event in the pathogenesis of EAOC

.

no alterations of ARID1A expression were

found in

the distal

nonatypical

endometriotic

tissue of the

same patients.

----



ARID1A

is a

tumor suppressor

gene, whose loss of expression leads to a

process of

precancerous transition.

Slide14

Activation of the PI3K/AKT pathway (

through

mutation of

PIK3CA and AKT or

inactivating mutations of

PTEN

) is

a frequent event in

clear-cell and

endometrioid

ovarian cancers

.

Activating

mutations in PIK3CA :

in 33–40% of clear-cell

loss

of PTEN

expression:

in 40% of clear-cell ovarian cancers

AKT2 amplification

:in

14%

Slide15

Mutations of the gene KRAS were found in

10–20% of EAOCs

.

In a more recent study,

KRAS

mutations

were identified in 29% of

EAOCs

but in only 3% of tumors in

which endometriosis

was not identified,

supporting

the

hypothesis that

KRAS mutations have an important role only in EAOCs

Slide16

Slide17

Slide18

Molecular and genetic outline of endometriosis-associated ovarian cancer

mutations alone cannot

explain their clinical and phenotypic distinctions

,

the

ovarian environment is likely to

play a

critical role

Slide19

Effect of Ovulation Inhibition on Ovarian Cancer Development

Ovarian cancer risk is higher

in:

nulliparous women,

with a history of “incessant ovulation

”

Long-term artificial

inhibition of ovulation can be obtained

during reproductive

life with the use of hormonal contraceptives.

About one-third of ovarian cancers are prevented by ever

use of

a hormonal

contraceptive.

The

longer the

woman uses

hormonal contraceptives the greater is the reduction in

ovarian cancer risk, with the use for about 15 years

reducing the

risk of ovarian cancer of about 50%. Interestingly,

this protective

effect continues for more than 30 years

after hormonal

contraceptive discontinuation

Slide20

Effect of Ovulation Inhibition on Ovarian Cancer DevelopmentAfter

5 years

of hormonal contraceptive use,

Beral

et

al.

showed

a risk

reduction:

22.1

% for serous, of 27.1%

for

endometrioid

, and of 21.3% for clear-cell carcinomas,

but only

a

nonsignificant

6.7% reduction for mucinous ones

.

A study

has estimated that women with endometriosis

benefit most

from long-term inhibition of ovulation with

hormonal contraceptives

, experiencing a risk

reduction of about

80% following

10 years of

use

.

Slide21

Multiple pregnancies reduce the risk for

OC.

Tubal sterilization

,

avoids menstrual reflux

in peritoneal

cavity,decrease

of ovarian

cancer risk (EAOCs and high-grade serous

cancers)

hysterectomy reduces the risk of ovarian

cancer

risk

for EAOCs and high-grade

serous cancers is also dramatically reduced

by

the use of hormonal

contraceptives

that reduce the exposure to both

ovulation and cyclic menstrual reflux.

continuous use of hormonal contraceptives

particularly in

a continuous fashion reduces the risk of

recurrence after

the conservative surgery of an ovarian

endometrioma

Slide22

in patients with ovarian

endometriosis

, methods to

inhibit ovulation and/or to

reduce retrograde

menstruation should be strongly

encouraged for :

the possibility to

protect from

endometrioma

recurrence

,

Protect

from the increased risk of transformation

in EOACs

,

Protect

from the general incidence of high-grade

serous ovarian

cancers,

Slide23

Slide24

the main epithelial ovarian cancer

histotypes

are classified as types I and II

.

Type I

: so called

endometriosis-associated tumors that include

endometrioid

, clear cell, and

sero

-mucinous carcinomas

.

Type II

:

tumors are mainly composed of high-grade serous carcinomas

(HGSOC

),

almost 70% of ovarian

carcinomas.

Among the EAOC, the

seromucinous

histotype

is

fairly rare

.

endometrioid

ovarian carcinomas (ENOC) and the clear cell ovarian

carcinomas (CCOC

) are the most frequent

histotypes

associated with endometriosis

.

Slide25

Women

with endometriosis are at about

tripled risk for CCOC and doubled risk for ENOC

Slide26

Early detection of endometriosis-associated ovarian tumorsAccording to

Exacoustos

et al

.

the “

typical”endometrioma

:

is a

unilocular

or

multilocular

(

one to

four

locules

) cyst

,

with homogeneous low-level echogenicity (ground glass echogenicity) of the

cyst fluid,

no solid parts, and no

papillations

with detectable

bloodflow

,

Papillary projections are protrusions of

solid tissue

into the cyst lumen with

a height of 3

mm

or

more.

Slide27

The ultrasonographic

characteristics of

endometriomas

may differ according to pre-

or postmenopausal

status

.

Endometriotic

cysts in postmenopausal women are more frequently multi-

locular

and less likely to exhibit ground glass echogenicity, as anechoic cyst fluid or

cystfluid

with mixed

echogenicity is often

observed.

Guerriero

et al. :

in older women

multilocular

cysts

and cysts with

papillations

and other solid components become more common, whereas

ground glass

echogenicity of

cystfluid

becomes less common compared to

endometriomas

observed

in younger

women

.

Interestingly, the maximal cyst diameter does not seem to vary

significantly with

age

Slide28

Nezhat

et

al.(2015) :

increase in

endometrioma

size

in

postmenopause

or during

hormonal therapy

in

premenopause

,

modification of

ultrasonographic

characteristics

, and

appearance of

mural node

formation

constitute ominous signs that require surgical

excision.

Relapsing

or

worsening pelvic

pain symptoms

such as newly developed dysmenorrhea and dyspareunia should further

increase

the index of

suspicion.

Advancing

age

(>45

years) and the size of

endometriomas

(>8 cm)

were

independent predictors

of development of ovarian cancer among women with ovarian

endometrioma

Slide29

At TVUS,

carcinomas arising from

endometriotic

cysts

generally show

a vascularized

solid

component.

Tanase

et

al.:

whereas

in premenopausal

women the

majority of mural nodular lesions observed within ovarian

endometriomas

were retracted

blood clots

, in

older women and

those with

larger cyst

diameters, mural nodules were more likely

malignant,especially

in case of

large nodule sizes and taller-than-wider

lesions.

Tani-guchi

et

al.2014:

the

rapid growth of an

endometrioma

and the presence of mural nodules

were

the most

reliable predictors of malignancy

Slide30

In the large series of Kuo et al.

[2017],

the frequency of unexpected EAOC in presumed

ovarian

endometriomas

was 0.14

%.

All

patients with malignancies were

aged >40

years and almost two

thirds of

them had

vegetations

within the ovarian cyst at preoperative ultrasonography

Slide31

Evaluation of all suspicious endometriomas

by

gynecologists or radiologists with specific oncological experience

may greatly increase the detection of those

cysts that require prompt surgical removal.

subjective

assessment in the hands of an expert

remains as accurate as any technique

for assessment

of adnexal masses by

sonography

.

Thus

, it is appropriate to consider referral to an expert

gynecologic

sonologist

when faced with a challenging or indeterminate adnexal mass”

Slide32

Management of perimenopausal women with ovarian endometriomas

Unfortunately, no robust information is available on the effect of surveillance compared with that

of surgery

(unilateral

salpingo

-oophorectomy or cystectomy/partial ovarian excision) on mortality

from EAOC

in patients with endometriosis/

endometriomas

.

According

to the results of a

case-control study conducted

by

Rossing

et al

.[2008

], the risk of invasive epithelial ovarian cancer varied according to

performance

of ovarian surgery after the diagnosis of endometriosis

.

In fact, with respect to

women without

a history of endometriosis, the OR of ovarian cancer was 1.6 (95% CI: 1.1e2.3) among

women with

endometriosis who did not undergo surgery and 1.2 (95% CI: 0.5e2.5) among those who

underwent

surgery.

Slide33

unilateral salpingo

-oophorectomy appeared protective (OR, 0.8;

95%CI

: 0.3e2.1), whereas cystectomy/partial ovarian excision was not (OR, 3.3; 95% CI: 0.7e15.3).

In

particular

, the OR of ENOC and CCOC was 3.2 (95% CI: 1.9e5.6) among women with a history

of endometriosis

with no subsequent ovarian surgery, compared to 1.6 (95% CI: 0.4e5.7) among

those who

underwent ovarian surgery. However, the small number of cases limited the precision of

the estimates.

only 94 women with a history of endometriosis were included in this study, and

only 20

of them underwent previous ovarian surgery

Slide34

case-control

study by

Melin

et al

.[2013],

all women with

a first-time

discharge diagnosis

of endometriosis in the period

1969-2007

were identified using the National Swedish Patient

Register, and

all women diagnosed with epithelial ovarian cancer at least one year after the

endometriosis diagnosis

(cases) were identified by linking to the National Swedish Cancer Register

.

A

significant

association was

observed between

unilateral

salpingo

-oophorectomy

, as well as radical excision of all visible endometriosis, and ovarian cancer

risk(adjusted

OR, 0.19; 95% CI 0.08e0.46 and 0.30; 95% CI 0.12e0.74, respectively).

Unfortunately

, no in-formation has been provided on ovarian cancer

histotype

; thus, the effect of unilateral

salpingo

-oophorectomy is expected. Moreover, the categorization of radical versus

nonradical

endometriosis

excision was based on retrospective review of surgical notes

Slide35

In case unilateral salpingo

-oophorectomy is performed, the risk of overall ovarian cancer

mortality is

reduced

by definition

, but this

effect may

be largely due to a decrease in the risk of death

from HGSOC

following salpingectomy, rather than from CCOC and ENOC following removal of ovaries with

endo-metriomas

. Therefore, the results of the above two studies do not definitively clarify whether surgery

specifically aimed at removing ovaries with

endometriomas

is better than surveillance, in terms of

reduced mortality from EAOC, for

perimenopausal

patients with endometriosis

Slide36

Management of perimenopausal women with ovarian endometriomas

two different clinical approaches may be envisaged in

perimenopausal

women

with small

(<5 cm), typical

endometriomas

:

(

i

) removal of the affected ovary/ovaries plus

bilateral salpingectomy

, especially in cases of long-standing

endometriomas

in women who are not using OC

or

progestogens

, or

(

ii)

strict

surveillance±progestogen

treatment with immediate surgery in case

of modifications

of

ultrasonographic

cyst patterns (e.g., cyst volume increase and appearance of

septa,papillary

projections, mural nodules, or changes in vascularization), or suspicious increase in serum

CA125 and(HE4

) levels.

Slide37

the results of

the

studies do not definitively clarify whether

surgery specifically

aimed at removing ovaries

with

endometriomas

is better than surveillance, in terms

of reduced

mortality from EAOC, for

perimenopausal

patients with endometriosis

case-control study conducted by

Rossing

et al.[2008

],

case-control

study by

Melin

et al.[2013],

Slide38

In theory, surveillance could be justified by the

fact that

endometriosis-associated cancers

usually remain

intracystic

for a variable period of time

Slide39

Surgery should be considered in case

of:

long-standing

endometriomas

,

especially

if they

are not being treated with oral contraceptives (OCs) or

progestogens

also

in the case of

denovo

detection of an

endometrioma

during medical treatment

, as the risk of malignancy appears

here substantially increased.

Size/age/

sono

/

Slide40

Not removing the ovary with endometriotic

cysts means that

perimenopausal

women should

undergo periodic TVUS and serum marker level measurements for many years. In addition, the

var-iable

degree of anxiety caused by knowing of being at increased risk for a dreadful cancer should be

carefully weighed.

Slide41

In case surgical abstention

is chosen,

progestogens

may be used as a therapeutic measure during surveillance,

A suspicious

modification of TVUS appearance or increase in cyst size

during suppressive

medical therapy

requires prompt

surgical exploration

Slide42

Surgery is obviously the

only reasonable choice when large and/or doubtful

endometriomas

are present

Slide43

While there appears to be an association between endometriosis and EOC,

endometriosis is not considered a premalignant lesion, and screening is not recommended

.

There are no data indicating that prophylactic removal of endometriosis lesions reduces the risk of EOC

.

Slide44

Slide45

Link to cancer — Endometriosis appears to be associated with some epithelial ovarian cancers (EOC) [163]; whether women with endometriosis are at risk for other types of cancers is unclear [164,165]. In a meta-analysis of 13 case-control studies including nearly 8000 women with EOC, women with a self-reported history of endometriosis had three times the risk of clear cell EOC and double the risk of

endometrioid

and low-grade serous EOC but no change in risk of high-grade serous or mucinous EOC [

166].

Slide46

Activation of oncogenic KRAS and

PI3K

pathways and inactivation of tumor suppressor genes

PTEN

and

ARID1A

have been suggested as mechanisms for the transformation of endometriosis, particularly ovarian

endometriomas

, to malignancy [163].