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Is Endometriosis a Precancerous Disease?
JUNG-HYE CHOI, PhD
Kyung Hee University
Choi’s lab
Research Directions:
A. Gynecological Oncology (Ovarian, Endometrial,
and Cervical Cancer)
- Rsf-1, p53 GOF mutation, pre-mir 886, PGI2, leptin…
• Chemoresistance, chemosensitizer
• Tumor microenvironment (Tumor-associated macrophage)
• Metastasis (adhesion, migration, invasion)
• Anti-cancer effects of natural products and their molecular mechanism of action
B. Endometriosis
• Adipokines in endometriosis
• Endometriosis peritoneal microenvironment
• Drug candidates: AdipoR1 agonist, natural products
University of
British Columbia
Endometriosis
Estrogen dependent inflammatory disease that
affect ~10 % of women in the reproductive age
25-30% of infertile women
40-70% of women with chronic pelvic pain
Presence of endometrium-like tissue in sites
outside the uterine cavity (primarily on the pelvic
peritoneum and ovaries)
Chronic pelvic pain, pain during menstrual cycle and intercourse,
infertility (25-35%), risk for some cancers
Estrogen-dependent inflammatory disease, complex chronic systemic
disease
Etiology
- Genetic: a polygenic manner ( ~7 times higher incidence) : chromosome 7/10
- Environmental toxins: dioxins, phthalates, bisphenol A or organochlorinated
pollutants
- Increased exposure to menstruation (ie. earlier menarche, shorter menstrual
cycles and nulliparity)
- Low body mass index (Vigano et al 2012)
Hypothesis
1) Retrograde menstruation (Sampson’s implantation hypothesis)
fragments of menstrual endometrium pass backward through the fallopian tubes and
then become implanted on peritoneal surfaces and persist there. (by molecular defects
or immunologic abnormalities)
2) Coelomic metaplasia
3) induction theory
4) Immunity
5) genetic
6) Others: Vasculogenesis
Endometriosis has been associated with several types of
cancer, autoimmune disease, asthma, and cardiovascular
disease over recent decades
=> Suggesting that endometriosis patients may represent a
high-risk group for these chronic disease.
Endometriosis and Cancer
Nezhat et al American Journal of Obstetrics & Gynecology (2015)
!  Characteristics of cells
Estrogen-responsive
/progesterone-unresponsive
Endometriosis
Proliferation
Apoptosis
Migration
Invasion
Inflammation
Angiogenesis
-recurrence
-hormone-dependent growth
Difference between endometriosis and cancer
- The invasion of endometriosis is controlled and stops at specific point of time.
- Also, endometriosis is attached and damage other tissues, but does not result in a
catabolic state
- Rarely fatal (It results in few deaths with this being estimated at 200 globally in 2013.[6])
History
Sampson documented the association of endometriosis
with malignant tumors in 1925 and outlined three criteria for
the diagnosis of malignant transformation:
1) The coexistence of carcinoma and endometriosis at the same site,
2) Histological similarities between the carcinoma and endometriosis
3) Exclusion of a malignant tumor elsewhere
In 1953, Scott established the additional requirement of
a continuum between benign and malignant epithelium
Recent publications
Endometriosis and cancer
Epidemiological Data
!  Malignant transformation of endometriosis is reported generally in 1% of
cases
!  Malignant transformation of endometriosis is more commonly in ovaries
than in extra-ovarian sites
!  Gynecological Cancer
•  Ovarian
•  Endometrial
•  Cervical
!  Breast Cancer
!  Melanoma
!  Non-Hodgkin’s lymphoma
Ovarian Cancer
!  Ovarian cancer has been the most consistently associated with endometriosis
!  Most epidemiological studies to date were case-control, retrospective cohort
design (specific population: cohort of endometriosis patients or women
evaluated for infertility)
!  Most of the studies reported a positive association (3/4 statistically significant)
Cohort study
Years Studies
1997
2002
2004
2005
2006
2007
2007
2010
2013
Brinton et al.
Olsen et al.
Brinton et al.
Brinton et al.
Melin et al.
Melin et al.
Kobayashi et al.
Aris
Stewart et al.
Entity of the association
(OR, SIR or RR or HR and 95%
CI)
1.92 (1.3–2.8) Cohort of post-menopasual women
0.78 (0.25–2.44)
2.48 (1.3–4.2)
1.69 (1.27–2.25)
1.43 (1.19–1.71)
1.37 (1.14–1.62)
8.95 (4.12–15.3)
1.6(1.12-2.09)
3.11(1.13-8.57) (for nulliparous
A cohort study by Melin et al. (2007)
! The data of 63,630 women with endometriosis between 1958 and 2002
were analyzed
! There was no increased overall risk of cancer (SIR 1.01)
! Significantly increased risk (SIR 1.37) was observed for ovarian cancer
Case-control study
Years Studies
2000
2002
2004
2004
2008
2008
2008
2009
2012
2013
Ness et al.
Ness et al.
Borgfeldt and Andolf
Modugno et al.
Rossing et al.
Merritt et al.
Nagle et al.
Wu et al.
Pearce et al.
Merritt et al.
Entity of the association
(OR, SIR or RR or HR and 95%
CI)
1.7 (1.2–2.4)
1.73 (1.10–2.71)
1.34 (1.03–1.75)
1.32 (1.06–1.65)
1.5 (1.1–2.1)
1.31(0.97-1.78)
3.0(1.5-5.9)
1.66(1.01-2.75)
1.46(1.31-1.63)
1.92(1.36-2.71)
A case-control study by Pearce et al. (2012)
! The data from Ovarian Cancer Association Consortium in a pooled analysis
of 13 case–control studies that included 7911 invasive ovarian cancer cases
and 1907 borderline ovarian tumors between 1992-2008
! Self-reported endometriosis was associated with a significantly increased
risk of ovarian cancer ( OR 1.46 , 95% CI 1.31–1.63)
A meta-analysis study by Kim et al. (2014)
! The data from 20 case–control and 15 cohort studies including 444,255
patients from 1 625 potentially relevant studies published online between
1990 and 2012
!  Endometriosis increased ovarian cancer risk in case–control or two-arm
cohort studies (RR, 1.265; 95% CI, 1.214–1.318) and single-arm cohort
studies (SIR, 1.797; 95% CI, 1.276–2.531)
! Stage I–II disease, grade 1 disease and nulliparity were more common in
EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367–2.807, 1.149–1.514
and 1.245–1.415),
Other Gynecological Cancers
Endometrial cancer
Study design
year
studies
Cohort
Cohort
Cohort
Cohort
Cohort
Case– control
Case–control
Case-control
1997
2002
2005
2006
2007
2004
2005
2015
Brinton et al.
Olson et al.
Brinton et al.
Melin et al.
Melin et al.
Borgfeldt and Andolf
Brinton et al.
Yu HC et al.
OR, SIR or
RR or HR
1.09
1.20
0.82
1.19
1.14
0.58
1.23
2.83
95% CI
0.6– 1.9
0.57– 2.53
0.3– 1.9
0.96–1.46
0.93–1.39
0.42– 0.81
0.63–2.38
1.49-5.35
!  Data on the association between endometriosis and endometrial cancer
was inconsistent
!  Low number of cases
Cervical cancer
Study design year
studies
OR, SIR
or RR or
HR
0.72
0.64
0.71
0.57
95% CI
Cohort
1997
Brinton et al.
0.4– 1.3
Cohort
2006
Melin et al.
0.47–0.84
Cohort
2007
Melin et al.
0.53–0.94
Case– contro 2004
Borgfeldt and Andolf
0.37– 0.9
l
0
!  All of the available investigations to data have reported reduced risks in
women with endometriosis
!  Low number of cases (all from Sweden)
Breast Cancer
!  The association between endometriosis and breast cancer still remains
unclear.
!  Most studies suggested a modest positive association between
endometriosis and breast cancer risk. However, some observed no clear
association and even reverse relation
!  No study analyzing the findings according to breast cancer type, hormone
receptor status or molecular subtype.
Study
design
Cohort
Cohort
Cohort
Cohort
Cohort
Cohort
Cohort
Cohort
Case– contr
ol
Case–contro
l
year
studies
95% CI
Schairer et al. (A)
Schairer et al. (B)
Brinton et al.
Venn et al.
Olson et al.
Brinton et al.
Melin et al.
Melin et al.
Moseson et al.
OR, SIR or RR or
HR
3.2
1.7
1.27
1.04
1.01
0.78
1.04
1.08
4.3
1997
1997
1997
1999
2002
2005
2006
2007
1996
1997
Moseson et al.
1.7
0.6–5.1
1.2– 8.0
0.7– 4.1
1.1– 1.4
0.71– 1.54
0.79– 1.29
0.6– 1.1
0.98–1.09
1.02–1.13
0.9– 20.4
Melanoma
! Among the eight studies, four studies reported a positive association while
four studies observed no association between endometriosis and melanoma
risk
Study design
Cohort
Cohort
Cohort
Cohort
Case– control
Case– control
Case– control
Cross-sectional
year
1997
2002
2005
2007
1989
1992
1995
2010
studies
Brinton et al.
Olson et al.
Brinton et al.
Kvaskoff et al.
Wyshak et al.
Frisch et al.
Holly et al.
Gemmill et al.
OR, SIR or RR or HR
1.0
0.7
2.1
1.62
3.9
1.1
0.9
3.81
95% CI
0.7– 1.5
0.2– 1.8
1.0– 4.4
1.15-2.29
1.2– 12.4
0.5– 2.3
0.5– 1.4
2.60-5.56
Non-Hodgkin’s lymphoma
!  Three cohort studies reported a positive association while one crosssectional study observed no association
!  Low number of cases
Study design
Cohort
Cohort
Cohort
Cross-sectional
year
1997
2002
2006
2010
studies
Brinton et al.
Olson et al.
Melin et al.
Gemmill et al.
OR, SIR or RR or HR
1.8
1.7
1.24
0.84
95% CI
1.2– 2.6
1.0– 2.9
1.02–1.49
0.14-3.37
Summary I
!  There was no increased overall risk of cancer among
women with endometriosis
!  Accumulating epidemiological data, from large cohort
and case-control studies, have demonstrated an
increased risk of ovarian cancer in women with
endometriosis. The effect sizes are between 1.3 and
1.9.
!  The incidence risk of breast cancer, melanoma, and
cervical cancer in women with endometriosis is still to
be verified.
Ovarian cancer: Deaths and Cases
-  Ovarian cancer is the second most common gynecological malignancy in
developed countries and the most lethal
-  Approximately 22,000 new cases of OVCA diagnosed each year and
14,000 cancer-related deaths (Siegel R et al. Cancer statistics, 2014 CA Cancer J Clin)
Ovarian cancer
Epithelial ovarian carcinomas, which consist approximately 90% of human
ovarian cancer, arise in OSE, tubal epithelium, endometrial tissue with the
rest originating in granulosa cells or, rarely, in the stroma or germ cells.
Histological subtypes of OEC/EOC
Serous (68~71%), Clear cells (12~13%), Endometrioid (9~11%)
et al Pathology
Mucinous (3%), Transitional (1%), Mixed histologies (6%) McCluggage2011
Anglesio et al (2013) Plos One
Prevalence of endometriosis in patients with ovarian cancers according to hist
ological subtypes
years
Authors
1971
Aure et al. [1]
Kurman and Craig
[7]
Russel [11]
0% (0/357)
Ovarian cancer histotype
endometrioi
Mucinous
Clear cell
d
1% (1/203) 24% (14/59) . 9% (20/212)
6% (7/118)
4% (2/47)
8% (2/28)
11% (4/37)
3% (7/233)
4% (3/69)
48% (16/33)
28% (20/72)
1993 Vercellini et al. [14]
4% (8/220)
6% (6/94)
21% (8/38)
6% (1/18)
41% (7/17)
39% (9/23)
45% (5/11)
9% (3/33)
3% (1/35)
6% (2/35)
0% (0/17)
3% (1/30)
6% (2/35)
50% (22/44)
41% (13/32)
54% (27/50)
70% (30/43)
14% (5/35)
9% (1/11)
0% (0/16)
...
67% (2/3)
...
6% (1/17)
8% (4/49)
...
36.8% (7/19)
30% (16/54)
23% (3/13)
42% (13/31)
43% (3/7)
20% (13/66)
22% (4/18)
31.6%
(12/38)
...
58.8% (10/17) 35.3% (6/17)
OR 3.05
2.04
20.2%
13.9%
1972
1979
Serous
De La Cuesta et al.
0% (0/10)
[12]
1996
Toki et al. [13]
10% (9/88 )
1997
Jimbo et al. [4]
9% (8/92)
1997 Fukunaga et al. [3]
10% (6/63)
2000
Ogawa et al. [8]
7% (4/60)
2000 Vercellini et al. [15]
3% (2/61)
2003
Oral et al. [9]
4% (3/70)
Dzatic-Smiljkovic
2011
3.5% (4/113)
et al. [2]
*
Kondi-Pafiti et al.
2012
5.9% (1/17)
* Low grade serous
[6] OVCA (OR: 2.11)
7.3%
1996
6.0%
Other
...
...
...
12% (11/88
26% (30/114)
)
...
...
20.2%
A meta-analysis study by Kim
et al. (2014)
! The data from 20 case–control
and 15 cohort studies including
444,255 patients from 1 625
potentially relevant studies
published online between 1990 and
2012
!  Endometriosis significantly
increased certain types of ovarian
cancer risk:
•  Clear Cell (RR 2.606;
•  95% CI 2.225-3.053)
•  Endometrioid (RR 1.759;
95% CI 1.551-1.995)
Two types of OEC
Kurman and Shih (2011) Human Pathology
Histological Data
Atypical endometriosis
- dysplastic characteristics that are different from typical endometriosis
- precancerous and strong association with EAOC
> Histology (Thomas and Campbell 21)
1) L arge hyperchromatic or pale nuclei with moderate-to-marked
pleomorphism
2) increased nuclear-to-cytoplasmic ratio
3) cellular crowding and stratification
Atypical endometriosis
"  ~8% of endometrioses contain atypical endometriosis.
"  In ovarian cancer, atypical endometriosis is present in 23% of
endometrioid carcinomas and in 36% of clear cell carcinomas (Fukunaga et
al. Histopathology 1997) .
"  Most atypical endometriosis show direct continuity with endometrioticassociated carcinoma, but are rarely seen in noncancer endometriosis .
"  Women with previously biopsy-proven atypia within endometriosis were
found to develop a EAOC in the same ovary some years later
"  The spatial and chronological association with endometriosis-associated
carcinoma suggest that atypical endometrioses are precancerous lesions,
as seen in atypical hyperplasia of the endometrium (Prefumo et al. Gynecol Oncol
2002).
Morphologic steps of tumor progression from endometriosis to
endometriosis-associated carcinoma
EM
Endometriosis
Inflammation Atypical Borderline Clear cell
EM
cancer
tumor
Atypical
Endometriosis
Borderline
Tumors
EndometriosisAssociated OVCA
Molecular Data
Endometriosis and EAOC
!  Monoclonal expansion
!  Chromosomal gain/ loss: LOH
!  Epigenetic alteration: Guo SW et al.
Epigenetics of endometriosis Mol Hum Reprod (2009)
!  Genetic alteration: mutation of tumor suppressor gene/ oncogenes
Molecular profile in endometriosis-associated ovarian cancer
Endometrioid cancer
Wnt/ß-catenin
PI3K/Akt/mTOR
Clear cell cancer
p110subunit of PI3K
BAF250a
BAF250a
HGF/MET
ER and PR
TERT promoter mutation
Gudducci et al 2014
absent
15.9% Wu RC et al
(J patholo)
Atypical endometriosis has been often detected in close association with clear cell
or endometrioid carcinoma. Atypical endometriosis and EAOC share molecular
alterations such as PTEN mutations [44,45], ARID1A mutations and up-regulation of
HNF-1b.
HNF1b induces chemoresistance in clear cell ovarian cancer cells
Cisplatin
Paclitaxel
HNF1b induces chemoresistance via regulating the ROS
production and the NFkB pathway
NFkB transcriptional activity
XIAP
Relative levels of COX2 mRNA
COX2
1.0
*
*
0.5
0.0
Con siRNA siRNA 1
siRNA 2
Yang et al. Cancer Research (2014)
MPSC1TR
A2780TR
Yang et al. Carcinogenesis (2012)
Molecular profile in endometriosis-associated ovarian cancer
Endometrioid cancer
Wnt/ß-catenin
PI3K/Akt/mTOR
Clear cell cancer
p110subunit of PI3K
BAF250a
BAF250a
HGF/MET
ER and PR
TERT promoter mutation
Gudducci et al 2014
absent
15.9% Wu RC et al
(J patholo)
Atypical endometriosis has been often detected in close association with clear cell
or endometrioid carcinoma. Atypical endometriosis and EAOV share molecular
alterations such as PTEN mutations [44,45], ARID1A mutations and up-regulation of
HNF-1b.
- ARID1A encodes BAF250a protein, that belongs to the SWI/SNF chromatin remodeling family and plays a major
role in several cell processes, including development, differentiation, proliferation and DNA repair (Reisman et al
Oncogene 2009).
- Loss of ARID1A expression has been found in eight of the 24 (33%) SMBTs versus one of the 32 (3.1%) BOTs
of other histological type, thus supporting the hypothesis that the SBMT is a member of ERONs (Wu et al. Int J
Gynecol Pathol 2012)
- ARID1A mutations-> truncating or missense mutations-> loss of BAF250a protein expression (Wiegand et al. N
Engl J Med 2010).
- Loss of ARID1A expression was an independent predictor for shorter progression-free survival in patients with
ovarian clear cell carcinomas treated with platinum based chemotherapy (Katagiri et al. Mod Pathol 2012).
2006
2011
2012
2014
2014
Three factors have been implicated in molecular/genetic
alterations for malignant transformation of endometriosis
Inflammatory factors
Hormonal
factors
Molecular/
Genetic
Alterations
Malignant transformation of
endometriosis
Oxidative
stress
Oxidative stress
!  Ngoˆ et al. found that endometriotic cells often displayed increased ROS production,
altered ROS detoxification and reduced catalase levels, associated with increased
cellular proliferation and activation of ERK1/2 pathway.
!  The abundant free iron present in
endometriotic cysts could lead to oxidative
stress and DNA mutations that ultimately
result in tumor development.
Hormonal Factors
!  Estrogen enhances the survival or persistence of endometriotic tissue,
whereas prostaglandins and cytokines mediate pain, inflammation, and
infertility.
!  Estrogen seems to be a mitogen both for endometriosis and ovarian cancer.
!  Direct and indirect epidemiologic evidence suggest that estrogen may be
carcinogenic to the ovary (Lacey et al. JAMA 2002)
!  A link between inflammation and estrogen production in endometriosis was
recently uncovered and describes a positive feedback cycle that favors
overexpression of key steroidogenic genes, most notably aromatase,
overexpression of COX2, and continuous local production of estradiol and
PGE2 in endometriotic tissue.
Bulun SE, “Endometriosis “ N Engl J Med. 2009 Jan 15;360(3):268-79.
Adipokines
(Adipocytokines)
Cytokines secreted by adipose tissue/ adipose tissue-derived hormones
(Greek=> adipo-, fat; cyto-, cell; and -kinos, movement)
Leptin, Adiponectin, Resistin, Visfatin, TNFα, IL-6, MCP-1
Leptin->
16kDa, increased in obese, pro-inflammatory
Adiponectin-> 30kDa, decreased in obese, anti-inflammatory
Mainly associated to the regulation of food intake and energy expenditure
An important link between obesity, insulin resistance, and related
inflammatory disorders
Role of leptin and adiponectin in the regulation of carcinogenesis as
a like between obesity and cancer
Leptin and adiponectin in Cancers : involved in proliferation, migration,
invasion, inflammation, and angiogenesis
Leptin and adiponectin in Endometriosis
Serum leptin and adiponectin
Controversial PMID: 23188112, 16055459
PMID: 10902797, 12773447, 19544117, 16269446, 20047585, 18958774,
PF leptin
10902797, 11387300 , 20504092,21848410
Increased leptin levels in peritoneal fluid of patients with endometriosis
PF adiponectin
Decreased adiponectin levels in peritoneal fluid of patients with endometriosis
PMID: 16135012
PF leptin and infertility
PMID: 18814918, 11543854
Peritoneal fluid leptin concentration in infertile patients with endometriosis is HIGH.
Peritoneal fluid leptin is associated with chronic pelvic pain but not infertility in
PMID: 16269446, 15808381
endometriosis patients.
Serum adiponectin and infertility
A trend towards higher HMW adiponectin serum levels in successful ICSI cycles
compared to implantation failures was observed PMID: 20504081
PF leptin and stage
A positive correlation was found between peritoneal fluid leptin levels and the
Hum Reprod. 2006 Mar;21(3):788-91
Arch Gynecol Obstet. 2009 Mar;279(3):361-4.
endometriosis stage.
Reverse correlation
Hum Reprod. 2003 Jun;18(6):1205-9.
Leptin and Cancer
Garofalo and Surmacz, (2006) Journal of cellular physiology,
Choi et al (2005) JCEM
Housa et al. (2006) Physiol Res
Leptin
ObR
Adiponectin
AdipoR1
Choi et al. Fertility and Sterility (2013)
Comparison of expression status of adiponectin, leptin, and their receptors
between ovarian endometrioma and normal endometrium
44/44
32/44
14/44
39/44
Choi et al. Fertility and Sterility (2013)
- Both short and long forms of leptin receptor were found to be expressed
in ovarian cancers.
- Treatment with leptin significantly stimulated the growth of estrogensensitive BG-1 cells via a ligand independent ERa pathway
Choi et al (2011) Carcinogenesis
Effect of leptin on cell growth in epithelial endometriotic cells
Oh et al. Molecular Human Reproduction (2013)
Involvement of JAK2/STA3 and ERK signaling in leptin-induced cell growth in
epithelial endometriotic cells
Oh et al. Molecular Human Reproduction (2013)
Effect of leptin on migration and invasion in epithelial endometriotic cells
Vehicle
10
Vehicle
10
1 (nM)
100
1
(nM)
100
Ahn et al. In revision
Involvement of MMP-2 in leptin-induced migration and invasion in epithelial
endometriotic cells
TIMP-2
Ahn et al. In revision
Inflammatory Factors
Tumor Microenvironment & TAM
Reciprocal Activation of Macrophages and
Paclitaxel-resistant Ovarian Cancer Cells
Tumor-associated MQ
Manuscript in preparation
Effect of endometriotic cells on MQ recruitment and expression
of M2 marker in activated MQ
PBMC
M2 markers
Relative expression of
IL-6 mRNA
Cytokine and chemokine profiles of CM from endometriotic
epithelial cells
Effect of MCP-1/CCR2 inhibition on MQ recruitment,
endometriotic epithelial cell growth, and nodule formation
*
Conclusion
!  Endometriosis seems to be a precursor of some subtypes of ovarian
cancer (EAOC: endometrioid and clear cell)
!  In addition to numerous epidemiological studies, histopathological and
molecular evidence to support the hypothesis is accumulating
!  Genetic/epigenetic alteration, hormonal/ inflammatory factors, and
oxidative stress were related to malignant transformation of
endometriosis.
!  However, present evidence is insufficient to conclude whether
endometriosis is a precursor of other cancer or not.
!  The molecular mechanism of the malignant transformation of
endometriosis to ovarian cancer should be studied in detail.
Acknowledgments
Priya
Kyung Hee University
Yun-Ji Seo, Ji-Hye Ahn, Seung Hyun Jung, YeongIn Yang, Ji-Hyun Kim, Je-Sung Lee, Yoonjin Cho.
Jong-Kyu Lee, Umma Priya
Catholic University of Daegu
Dr. Hoon Kyu Oh
Dr. Youn Seok Choi
University of British Columbia
Dr. Peter C. K. Leung
Dr. Nelly Auersperg
Johns Hopkins University
Dr. Ie-Ming Shih
Dr. Tian-Li Wang
Cheil hospital (Kwandong Univ.)
Dr. Tae-Jin Kim
University of Texas
Dr. Yong Sun Lee (UTMB)
Dr. Ju-Seog Lee (MD anderson CC)
Cell lines
Dr. Anna Starzinski-Powitz, Dr. Graciela
Krikun, Dr. Asgi Fazleabas
Funding
The Korean Health Technology R&D Project, Ministry
of Health & Welfare (No. A111881, HI14C2416)
NRF (2010-0004306, 2013R1A2A2A01067888)
Based on the available information , clinicians should first
try to identify patients with endometriosis and follow
closely especially those that have higher chance of
malignant transformation These include:
-Women with long-standing history of endometriosis
-Endometriosis diagnosed at an early age
-Endometriosis associated infertility and/or history of
infertility treatment
-Ovarian endometrioma
“Malignant transformation of endometriosis and its clinical significance”
Nezhat et al Fertility and Sterility (2014)
Prat J, Vrchos Arch (2012) 460
What is MCP-1?
-  Monocyte chemotactic protein-1 (MCP-1)
-  Chemokine (C-C motif) ligand 2 (CCL2)
-  small inducible cytokine A2
-  13kDa, a small cytokine that belongs to the CC chemokine family
-  CCL2 recruits monocytes, memory T cells, and dendritic cells to the
sites of inflammation produced by either tissue injury or infection
- CCL2 is primarily secreted by monocytes, macrophages and dendritic
cells
- an active role in chemotaxis, angiogenesis, cellular proliferation,
differentiation, apoptosis, and inflammation
- the concentration of MCP-1 in peritoneal fluid and serum in women with
Am J Obstet Gynecol, 175 (1996); Gynecol Obstet Invest, 54 (2002); Blood, 78
endometriosis is high
(1991); Fertil Steril, 67 (1997
- Strong correlation between peritoneal MCP-1 level and stage of disease/
Fertil Steril, 67 (1997), Hum Reprod, 13 (1998)
severity of endometriosis
The American Journal of Pathology, 170(2), 2007
Hypoxia
Leptin
ESC
Eur J Gynaecol Oncol. 2015;36(1):21-4.
Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated
clinical features and study on molecular mechanisms involved in the possible
causality.
Machado-Linde F, Sánchez-Ferrer ML, Cascales P, Torroba A, Orozco R, Silva Sánchez Y,
Nieto A, Fiol G.
Abstract
PURPOSE OF INVESTIGATION:
To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and
explore the differences between women with endometrioid and clear-cell histologic subtypes
with and without associated endometriosis.
MATERIALS AND METHODS:
The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la
Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed.
RESULTS:
Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with
the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22
(32%). The prevalence of an association with endometriosis according to histologic type was
28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma.
CONCLUSION:
Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis.
Patients with endometiosis associated ovarian cancer differ from non-endometiosis
associated ovarian cancer in their clinical characteristics.
Three forms of endometriosis
1)  Peritoneal endometriosis: endometriotic implants on the surface of
the pelvic peritoneum and ovaries
2)  Endometrioma: ovarian cysts lined by endometrioid mucosa
(endometriotic tissues)
3)  Rectovaginal endometriotic nodule: a complex solid mass
comprised of endometriotic tissue blended with adipose and
fibromuscular tissue, residing between the rectum and the vagina
Three forms of endometriosis: 1)peritoneal endometriosis,
2) endometrioma, 3) rectovaginal endometriotic nodule
=> comment histologic features : presence of endometrial stromal or
epithelial cells, chronic bleeding, signs of inflammation. increased risk of
infertility or chronic pelvic pain.
The risk of ovarian cancer associated with different t forms of
endometriosis remains to be determined!!!
Chronic pelvic pain, pain during menstrual cycle and intercourse,
infertility (25-35%), risk for some cancers
Effect of endometriotic cells-CM on mRNA expression of M1/M2 penotype makers
and factors in macrophages
Clinical management of advanced OVCA:
Maximal cytoreductive surgery + paclitaxel and platinumbased chemotherapy
Clear cell cancer: Poor Prognosis
!  Less sensitive to the chemotherapy
!  a high degree of recurrence,
!  frequent early metastasis
!  resistance to chemotherapy
ARID1A Expression in Ovarian Clear Cell Carcinoma with an Adenofibromatous Component.
Nishikimi K, Kiyokawa T, Tate S, Iwamoto M, Shozu M. Histopathology. 2015 Apr 23.
The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign
endometriosis.
Chene G, Ouellet V, Rahimi K, Barres V, Provencher D, Mes-Masson AM. Int J Gynaecol Obstet. 2015 Apr 11.
Loss of ARID1A expression is associated with poor prognosis in patients with stage I/II clear cell carcinoma of
the ovary.
Itamochi H, Oumi N, Oishi T, Shoji T, Fujiwara H, Sugiyama T, Suzuki M, Kigawa J, Harada T. Int J Clin Oncol.
2015 Mar 6.
Decreased ARID1A expression correlates with poor prognosis of clear cell renal cell carcinoma.
Park JH, Lee C, Suh JH, Chae JY, Kim HW, Moon KC. Hum Pathol. 2015 Mar;46(3):454-60.
Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic
inflammatory cytokine signalling. Chandler RL, Damrauer JS, Raab JR, Schisler JC, Wilkerson MD, Didion JP,
Starmer J, Serber D, Yee D, Xiong J, Darr DB, Pardo-Manuel de Villena F, Kim WY, Magnuson T. Nat Commun.
2015 Jan 27;6:6118.
Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse
transcriptase promoter mutation.
Huang HN, Chiang YC, Cheng WF, Chen CA, Lin MC, Kuo KT. Mod Pathol. 2015 Feb;28(2):303-11
Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition.
Samartzis EP, Gutsche K, Dedes KJ, Fink D, Stucki M, Imesch P. Oncotarget. 2014 Jul 30;5(14):5295-303.
Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with
high ARID1A mutation rates.
Here we present a mutant mouse model of OCCC. We find that ARID1A
inactivation is not sufficient for tumour formation, but requires concurrent activation
of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice
develop highly penetrant tumours with OCCC-like histopathology, culminating in
haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic
treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by
inhibiting the tumour cell growth. Cross-species gene expression comparisons
support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We
further show that ARID1A and PIK3CA mutations cooperate to promote tumour
growth through sustained IL-6 overproduction.
Our findings establish an epistatic relationship between SWI/SNF chromatin
remodelling and PI3K pathway mutations in OCCC and demonstrate that these
pathways converge on pro-tumorigenic cytokine signalling. We propose that
ARID1A protects against inflammation-driven tumorigenesis.
Pathological studies
- morphological continuum of sequential steps during tumor progression from normal
endometriotic cyst epithelium to invasive endometrioid or clear cell carcinoma [33–
37].
- Atypical endometriosis, which is considered to be the earliest step in the malignant
transformation of endometriosis, is characterized by cytological atypia, with
eosinophilic cytoplasm, large hyperchromatic or pale nuclei with moderate to marked
pleomorphism, increased nuclear to cytoplasmic ratio, cellular crowding, stratification
or tufting [34,37].
- Women with previously biopsy-proven atypia within endometriosis were found to
develop a clear cell or endometrioid carcinoma in the same ovary some years later;
thus, confirming the chronological association between these two conditions [38–41].
A greater understanding of the pathogenesis of endometriotic-associated
carcinoma will better inform research into ovarian cancer prevention strategies
Malignant transformation of endometriosis
Pathophysiology that leads to malignant transformation of endometriotic foci
is not well understood.
> Two hypothesis
- Genetic defects allowing endometriotic implants to thrive and malignantly
transform
- Defects in immune function allowing endometriosis to grown leaving the
patient more susceptible to subsequent malignant transformation
> Carcinoma associated with endometriosis are usually a lower stage, are in
a younger population, and have a better prognosis than similar tumor
unrelated to endometriosis.
> About 90% of cases of extraovarian endometriosis lead to endometrioid
adenocarcinomas, with only a few reported examples of clear cell carcinoma
Hepatocyte nuclear factor-1β (HNF-1β)
Loss of ARIDIA / BAF250a
cancer-related genes
PTEN, KRAS, p53, CTNNB1
inflammation
IL-1, IL-6, IL-8, TNF-α, PGE2, C
OX-2
VEGF, RANTES, MCP-1, NFkB
hormonal factors
PGE2 –> estrogens
detoxifying enzymes
CYP1A1, CYP19, GALT, GSTM1
metastasis
MMP-2 , MMP-9 , Catenin ,
E-cadherin
DNA repairs or mutations
GALT , GSTM
suppression of pre-apoptotic gene Bax
and/or upregulation of anti-apoptotic gene Bcl-2
Possible mechanisms responsible for the malignant
transformation of endometriosis
Possible mechanisms responsible for the malignant
transformation of endometriotic lesions Malignant cells
exploit the cells’ intrinsic mechanisms to regulate the length
of its lifespan and its metabolism to their own advantage.
As oxygen, heat and fuel constitute the fire triangle, we
propose the endometriosis-induced carcinoma (EIC)
triangle (Figure 1). The three factors which directly
contribute to endometriosisinduced oncogenesis are (1)
alterations within the endometriotic cells’ genome, (2)
endocrinological factors and (3) immunological factors. The
relationship between inflammation, genetic influences and
cancer has been described by Balkwill et al. [25], as the
genetic influences being “the fuel that feeds the flame” and
inflammation being the “fuel that feeds the flame.” However,
in endometriosis, there is also the endocrinological
component which interacts with the genetic influences, in
addition to the immunological factors. In effect, the high
local levels of oestrogen in the ovarian endometriotic foci,
due to the upregulation of aromatase cause an increase in
the level of prostaglandin E2 (PGE-2) [53], which in turn
suppresses normal immunologic responses such as
phagocytosis [54] and leads to diminished apoptosis [55].
The increased levels of local oestrogens increases the level
of expression of angiogenic
AEM indicates atypical endometriosis; CCC, clear cell carcinoma; EAC, endometriosisassociated ovarian cancer; EBT, endometriosis-associated borderline tumor; EMC,
endometrioid carcinoma; EMS, endometriosis; MSI, microsatellite instability.
Endometriosis requires 4 to 10 years for water blister lesioins to progress to scarred blue-domed cysts, 7 to years
progress from clear to red to scarred black lesions, and approximatel 20 years for the proportion of scarred black
lesions to increase from 23% to 63% (12).
Most endometriosis encounter an unfavorable microenvironment and eventually regress.
Am J Obstet Gynecol. 1997 Mar;
176(3):572-9.
Published cross-sectional studies regarding the
relationship between endometriosis and ovarian cancer
Years
Studies
1993
1997
1997
2000
2000
2003
2011
2012
Vercellini et al. [23]
Jimbo et al. [24]
Fukunaga et al. [25]
Ogawa et al. [26]
Vercellini et al. [27]
Oral et al. [28]
Dzatic-Smiljkovic et al. [29]
Kondi-Pafiti et al. [30]
Entity of the association
(OR, SIR or RR or HR and
95% CI)
2.37
3.22
6.03
7.80
14.63
1.59
2.35
1.19
Breast cancer
Three possible explanations for the slight, if any, increase in breast cancer risk
among women with endometriosis, especially premenopausal ones
! the two disease may share a common pathogenetic insult of note, both
conditions have an hormonal-dependent etiology
! endometriosis, a possible cause of infertility, is particularly evident in
nulliparous women or in women who have delayed childbearing, both risk factors
for breast caner
! treatment of endometriosis with medications such as danazol, progestational
agents, and oral contraceptives could have an adverse Somigliana
effect on the
etbreast
al. 2006
Non-Hodpkin’s
(1) Humoral immunity abnormalities have been documented in women with
endometriosis. More specifically, there may be a link between B-cell activation
in endometriosis and development of B-cell lymphoma
(2)  the association may be consequent to medications prescribed to treat
endometriosis
(3) the link between the two conditions may be due to a common etiological
agent
Olson JE, Cerhan JR, Janney CA, Anderson KE, Vachon CM, Sellers T.
“Postmenopausal cancer risk after self-reported endometriosis diagnosis in the
Iowa women’s health study 2002 94 1612-1618
HNF1B
Detoxification
GPx3, GCLc, GCLM
ROS
NFkB
Chemoresistance
Anti-apoptotic
Bcl-2, XIAP
Two types of OEC
Type I vs Type II
Prat J, Vrchos Arch (2012) 460
Adenomyosis
a common benign pathology that is defined by the presence of endometrial
glands and stroma within the myometrium.
!  It has been reported that adenomyosis is associated with endometrial cancer
(Boes et al., Pitfall in the diagnosis of endometrial cancer: case report of an
endometrioid adenocarcinoma arising from uterine adenomyosis. Eur J Gynaecol
Oncol 2011; Musa et al., Does the presence of adenomyosis and lymphovascular
space invasion affect lymph node status in patients with endometrioid
adenocarcinoma of the endometrium? Am J Obstet Gynecol, 2012).
! 
Is adenomyosis associated with the risk of endometrial cancer?
Med Glas (Zenica). 2012 Aug;9(2):268-72.
This study was carried out retrospectively on pathologic specimens of hysterectomies.
statistically significant association of the presence of adenomyosis with uterine myoma
(p = 0.227) and endometrial polyps (p = 0.997) and endometrial carcinoma (p = 0.771)
was not found.=>hysterectomy specimens, no statistically significant difference was
determined between the groups with and without adenomyosis in terms of cooccurrence with endometrial carcinoma.
Malignant changes in adenomyosis in patients with endometrioid
adenocarcinoma Eur J Gynaecol Oncol. 2011;32(2):182-4.
Kucera E, Hejda V, Dankovcik R, Valha P, Dudas M, Feyereisl J
The aim of our retrospective study was to evaluate pathological changes in
adenomyotic foci in hysterectomy specimens, and point out a possible mechanism of
carcinogenesis in adenomyotic foci inside the myometrium.
Malignant changes in adenomyosis were present in 6.8% of patients with endometrial
cancer. All malignancy-positive cases of adenomyosis were associated with
endometrioid adenocarcinoma of the eutopic endometrium.
Leiomyomas
! Uterine LM (uterine fibroid) is a common neoplasm. It occurs in nearly 40% of
women of reproductive age
! Data came from a population-based, case-control study which included 1399 women
with endometrial cancer diagnosed between 2005 and 2007 and 1539 controls.
! Leiomyosarcomas (LMS) are the most common sarcomas that are reported to be in
only 0.1-0.3% of LMs.
! A self-reported history of uterine fibroids was associated with an increased risk of
endometrial cancer (OR=1.39; 95% CI: 1.10–1.74). This association was reduced for
women with body-mass index≥35 kg/m2 (OR=0.71; 95% CI: 0.37–1.37), and
increased in groups normally thought to be at low risk including women with normal
BMI (OR=1.66; 95% CI: 1.14–2.41) and premenopausal women (OR=1.82; 95% CI:
0.99–3.32).
Leptin receptor
Expression of leptin receptor in normal endometrium, eutopic endometrium,
ectopic endometriotic stromal tissue, peritoneal macrophage Mol Hum Reprod. 2002 May;8(5):456-64.
Function
Leptin stimulates the proliferation of endometrial and endometriotic
stromal cells
Mol Hum Reprod. 2002 May;8(5):456-64.
Treatment of peritoneal macrophages with leptin induced COX-2 expression.
production of prostaglandin F(2alpha) by peritoneal macrophages was increased
Am J Reprod Immunol. 2010 63(3):214
after leptin stimulation.
Increased leptin levels in peritoneal fluid from endometriosis patients may affect
local
PMID: 18814918
inflammatory/immune reactions, especially infiltration of CD4+ T helper cells.
Ablation of leptin signaling disrupts the establishment, development, and PMID: 17962343
maintenance of endometriosis-like lesions in a murine model.Endocrinology. 2008 Feb;149(2):506-14.